EPILEPSY GENETICS Newsletter ISSUE NUMBER 4 2005 PILEPSY ESEARCH E R elcome to the 2005 edition of the experience from their countries, and we C ENTRE WEpilepsy Genetics Newsletter. We all benefit enormously from the Austin Health like to keep you informed of all our excit- opportunity to exchange ideas. Heidelberg Repatriation Hospital, ing developments from our last year of Sadly, during 2004 we said farewell to Banksia Street,West Heidelberg, hard work here at the Epilepsy Research Centre at Austin Health,Melbourne and the several members of our team. Dr Lata Victoria 3081 University of Melbourne. We also take this Vadlamudi moved to become an academic Tel: (03) 9496 2737 opportunity to thank all of our five and a neurologist in Canberra where she will Fax: (03) 9496 2291 half thousand research participants and complete her PhD thesis, and Dr Nigel Tan Email: [email protected] supporters for their time and energy in returned to Singapore after spending 18 Website: www.epilepsyresearch.org.au helping our research to continue. Without months with us. We hope to keep working their kind assistance and enthusiastic closely with both Dr Vadlamudi and Dr Tan attitude to the research, our continuing in the coming years. Two research success and progress in the field would assistants, Sarah McInnes and Deborah not be possible. Keay (Glencross), also left the team during 2004. The research team, headed by Professor Sam Berkovic and Associate Professor Our work in the area of the genetics Ingrid Scheffer, is now in its 16th year and of epilepsy continues to progress well we continue striving to unravel the with a number of important scientific Professor Samuel Berkovic inheritance of seizures in both families and publications throughout the year. This twin studies. The last couple of years have ongoing success is made possible by our also seen our interest expand to strong collaborative links with researchers interrelated areas of research including from hospitals across Melbourne,Australia cerebral malformations and pharmacoge- and around the world. In particular our netics (how genes influence the way the collaboration with the molecular genetic body handles drugs). laboratory headed by A/Prof John Mulley THE TEAM at the Women’s and Children’s Hospital in We have had a number of additions to the Adelaide is integral to our success. Associate Professor Ingrid Scheffer genetics team in 2004. Kate Lawrence and More information about the Epilepsy Katie Kron are our new research Research Centre, the range of research assistants, both involved in conducting studies performed here and also Family Studies,with Kate also coordinating information for patients seeking treatment Twin Studies. We also have the pleasure of for their epilepsy through Austin Health RECENT NEWS hosting three international fellows; can be found on our website: paediatric neurologists, Dr Floor Jansen Our research investigating www.epilepsyresearch.org.au. (Utrecht, The Netherlands), Dr Yue Hua changes in the SCN1A gene in The website contains previous editions of (Helen) Zhang (Beijing, China) and adult people with Severe Myoclonic this newsletter and helpful links for neurologist, Dr Gunay Gul (Turkey), who Epilepsy of Infancy (see page 2) more information about epilepsy. If you are each spending six months with our has been a major contributor to have any specific queries for us we group learning more about epilepsy and the development of a diagnostic can be contacted by email at research into epilepsy genetics. Dr Zhang, [email protected]. test for this gene becoming Dr Jansen and Dr Gul bring valuable commercially available. Many patients who have been involved in our research have already been tested for changes in this gene. The Epilepsy Research Centre genetics team 2004 SCN1A PROGRESS R EPORT ur last two newsletters highlighted thought changes in this gene might be the recently gave two information sessions Oour recent work studying the gene cause of other forms of severe epilepsy. on Severe Myoclonic Epilepsy in Infancy. that encodes the alpha-one subunit of the We originally aimed to study approximately A small group was organised by the neuronal sodium channel, SCN1A, in 100 patients, but due to demand from all Epilepsy Association of South Australia in patients with a severe type of epilepsy around the world, we now have close to Adelaide, whilst we organised a gathering called Severe Myoclonic Epilepsy of 250 patients enrolled. This has meant a at Austin Health for about 20 parents and Infancy (SMEI). delay in finalizing this complex set of grandparents of children involved in our results and we thank the study partici- SCN1A research including one Tasmanian We have extended this study further and pants for their patience. family. The gatherings were an have been looking for changes in this opportunity for family members to be gene in patients not only with SMEI, but In order to thank the local families who able to share their experiences with also with other severe epilepsies kindly participated in this major study others, whilst learning more about SMEI. beginning in the first year of life. We Associate Professor Ingrid Scheffer IDIOPATHIC GENERALISED EPILEPSY STUDY his year we began collaborating with Idiopathic Generalised Epilepsies are there are likely to be a number of genes Tthe Gene Mapping Centre in Berlin, thought to be genetic, even though most that contribute together to produce a Germany, headed by Dr.Thomas Sander. cases do not have a family history of specific epilepsy syndrome. We hope The aim of this collaboration is to identify epilepsy. IGEs are relatively common, the genome scan will identify gene new genes that are involved in causing accounting for about 20-30% of people combinations that may cause susceptibility several of the common Idiopathic with epilepsy. Seizures generally to these epilepsy syndromes. Generalised Epilepsies (IGEs) such as begin during childhood or Childhood Absence Epilepsy (CAE), adolescence, although some Juvenile Absence Epilepsy (JAE), and people first experience Juvenile Myoclonic Epilepsy (JME). DNA seizures in adulthood. People from 35 of our Australian and Israeli with IGE are of normal families was sent to the Gene Mapping intelligence, do not have Centre to undergo a genome wide scan structural brain abnormalities, to identify chromosome regions likely to and often outgrow their contain epilepsy genes. Because of the seizures, such as in CAE. statistical methods used to analyse the Some examples of the families data, we only included families where two Because of the variety of IGE included in the Idiopathic or more siblings have IGE. syndromes within families, Generalised Epilepsy study B ENIGN R OLANDIC E PILEPSY – ISITG ENETIC? enign Rolandic Epilepsy (BRE) is the on 1761 twin pairs from Australia, seizures themselves. most common childhood epilepsy Denmark, Norway and the United States B Together with our colleagues at the syndrome thought to have a genetic basis. and found no cases of twins who were Brain Research Institute at Austin Health In the past, researchers have published concordant for BRE. This indicates that we are studying MRI brain images of articles about twin pairs who are although patients with BRE may still children with Benign Rolandic Epilepsy, concordant (both have) for BRE, have an underlying genetic predisposition as well as collecting clinical information suggesting that this particular epilepsy to seizures, other, so far unidentified and blood samples for future genetic syndrome is highly genetic. factors, must be contributing to their studies to help us better understand epilepsy. Indeed, we believe it may be During 2004 Dr. Lata Vadlamudi travelled this condition and the impact it has the characteristic EEG feature of to a number of countries to identify cases on children’s lives. centro-temporal spikes seen in BRE that of BRE in databases of both identical and has a genetic basis rather than the non-identical twins. She reviewed data E PILEPSY AND B RAIN M ALFORMATIONS ertain genes, which are switched on the brain) of patients with different types these malformations, and hopefully Cin the early stages of embryonic of structural abnormalities, where the lead to identification of the causative development, regulate how neuronal cells causative genes have not yet been found, genes.We hope that by identifying migrate and form the human brain. It is were sent to the Walsh Laboratory. This genes linked to these disorders we likely that mutations in these genes affect information will help the laboratory can learn more about how the brain cell migration and give rise to structural better define the conditions caused by develops and better counsel patients abnormalities in the brain, or malforma- and their families regarding these tions. Seizures may occur secondary to disorders. these malformations. MRI of a brain We have a long-standing collaboration showing a with the Walsh Laboratory at the Harvard malformation Institutes of Medicine (USA), who lead the called field in malformations genetics research. polymicrogyria In the past we have studied some families In normal brain development cells migrate (arrows) where with certain malformations and have from the middle of the brain to the outside normal folding successfully collaborated with the Walsh edge (Figure A). In brain malformations cells of the brain lab, and with other groups overseas, to may never migrate (grey circle, eg periventric- surface is replaced by lots of small, abnormal identify genes causing brain malformations ular heterotopia), or may not reach the edge folds. and seizures. Earlier this year, a collection (black line, eg double cortex) (figure B). of DNA samples and MRI’s (pictures of ABCB1 IN T EMPORAL L OBE E PILEPSY he ABCB1 gene is important for the findings of the UK group, despite other words, although Italians may be at Ttransporting drugs in and out recruiting a group of patients that was risk if they had this GABBR1 variant, other of the brain.