Australasian Science: Australia's authority on science since 1938

The genetics of epilepsy: bringing hope to families

Sam Berkovic and Ingrid Scheffer have changed the way the world thinks about epilepsy, the debilitating condition that affects about 50 million people.

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.

The two clinician-researchers from the University of Melbourne have led the way in finding a genetic basis for many epilepsies, building on their discovery of the first ever link between a specific gene and a form of epilepsy. Finding that answer has been of profound importance for families.

Along the way, Sam and Ingrid discovered that a particularly severe form of epilepsy, thought to result from vaccination, was actually caused by a gene mutation. This finding dispelled significant concerns about immunisation.

Their discoveries of the connections between epilepsy and genes have opened the way to better targeted research, diagnosis and treatment for epilepsy. Together with collaborators, they have shown that genes can lead to seizures in different ways in different forms of epilepsy. An important cause, for instance, is interference with the movement of nutrients across nerve cell membranes. In one of these cases, treatment using a diet that avoids glucose is effective.

For their contribution to the study of epilepsy, its diagnosis, management and treatment, Laureate Professor Sam Berkovic of the University of Melbourne and Austin Health and Professor Ingrid Scheffer of the University of Melbourne and the Florey Institute of Neuroscience and Mental Health and Austin Health have been awarded the 2014 Prime Minister’s Prize for Science.

Around 9.15 pm on any given Tuesday, Sam Berkovic rings Ingrid Scheffer. That’s roughly 15 minutes after he finishes his consultations with adult epilepsy patients. Ingrid’s last appointments with her mainly child and adolescent patients wind up a little earlier in the day.

Over the phone they compare notes on what they have seen and begin floating ideas for critical review, eventually deciding what is worth taking to their research group for discussion about further study and experimentation. This is the beginning of a time-honoured process which has made them leaders in their chosen field of epilepsy research.

They and their colleagues have tracked down 13 of the 23 genes known to be directly linked with forms of epilepsy. The work involves some of the latest molecular and genomic biology techniques. As physician–researchers, they collaborate closely with basic scientists, including geneticists, bioinformaticians and neurophysiologists in Australia and overseas to find and understand the genes and how they cause epilepsy. Ingrid and Sam’s core research is concerned mainly with 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.

It all started when Sam was doing postdoctoral work in the mid-80s at the Montreal Neurological Institute, a world centre for epilepsy research. There he worked with Fred and Eva Andermann, a neurologist and neuro-geneticist respectively. “I learned about genetics and epilepsy from them, almost by osmosis,” Sam says. Through Eva, he also gained access to the pioneering twin studies on epilepsy of American researcher William Lennox. 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.

By the time Sam left Montreal to come back to Australia in 1987, he was already setting up an epilepsy study with the National Health and Medical Research Council’s Australian Twin Registry. He is still working on that study. By 1991, when he agreed to supervise the PhD studies of Ingrid Scheffer, fresh from training as a paediatric neurologist in the UK, he already was convinced of significant genetic involvement in epilepsy by the twin evidence he had accumulated. He wanted to extend his genetic studies to large families, and that’s what Ingrid’s research project was about.

Sam and Ingrid discovered a large family in South Australia, 27 members of which suffered from epilepsy. They carefully detailed the type of epilepsy in each family member and this led to the first of many novel epilepsy syndromes they have described. By 1995, with the help of Professor Grant Sutherland, Professor John Mulley and colleagues at the University of Adelaide, the problem was traced to chromosome 20 and then to a particular region of that chromosome.

One of Sam’s fondest memories is of sitting in his study taking a phone call from a collaborator in Germany who had finally nailed the gene they 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 such ion channels.

After two children and much research work while still practising as a child neurologist at the Austin Hospital, Ingrid published her PhD thesis in 1998. In it she described four new epilepsy syndromes based on families. The gene for each one has now been discovered.

The importance of unearthing genetic links for epilepsy goes beyond providing peace of mind to people with epilepsy and their carers. For instance, the two researchers have shown that a particular gene, which codes for a protein that transports the important energy source glucose into nerve cells, 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. Together with a dietician and UK colleague, Ingrid has written a cookbook for people on this special diet.

The story of how they revealed the basis of ‘vaccine encephalopathy’—epilepsy seemingly caused by vaccination—is a good illustration of the way their partnership can work. Dravet syndrome is a severe epilepsy in which Ingrid has long had an interest. It begins in infancy 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 to Ingrid about Dravet syndrome, Sam suddenly realised that one of his long-term ‘vaccine encephalopathy’ patients had the condition. Together, the two of them tracked down a genetic basis for the vaccine-related disease and deepened the understanding of Dravet syndrome. They found that epilepsy was inevitable for those with the wrong genetic signature. Vaccination was just one possible trigger.

Their research also has exposed the presence, prevalence and importance of de novo gene mutations. These are changes in gene sequences that have not been passed on by the parents. They arise newly in offspring. They can happen, for instance, during the cell replication process and can cause several forms of epilepsy.

Sam and Ingrid both agree that the strength of their partnership lies partly in their ability to communicate and bounce ideas off each other and partly in their different backgrounds and perspectives—one concerned with adult epilepsy, the other with childhood; one male, the other female; Sam linking syndromes back to basic science, Ingrid describing and delineating those syndromes. They have become very close friends, and trust each other’s thoughts and instincts.

Although both researchers already have been recognised through winning significant awards for epilepsy research, being elected fellows of the Australian Academy of Science, and awarded the Order of Australia, it has never been at the same time. Their partnership has never fully been recognised.

This is one award they can enjoy together.

Science in Public