Project Lead

Professor Ingrid Scheffer AO

Lead partner

The University of Melbourne


Austin Health; Florey Institute of Neuroscience and Mental Health; Royal Children’s Hospital; Walter and Eliza Hall Institute

Project summary

Download PDF

For most children there is a genetic cause of EE and in 50% of cases the gene involved has been identified. But the problem is very complex and overall more than 100 genes are involved.

This project will expand on an existing patient group of more than 700 to help understand which genes cause their disease and, of those, which ones might provide opportunities for new therapies. Stem cells derived from the patient group will be utilised to safely test new pharmaceutical treatments. There are elements of how epilepsy works that are well understood. This project will also investigate the use of existing drugs that have been developed for other conditions to determine their value in treating epilepsy. Because these drugs are already in the market and are safe, they can be rapidly repurposed if useful. Importantly, the research team already has strong working relationships with the families of the children involved – a critical factor in successful trials of this type.

With an aim to end the ‘diagnostic odyssey’ for patients with developmental and epileptic encephalopathies and their families through providing a definitive diagnosis, the project has led to improvements in:

1) Diagnosis
Patients in the study received their first diagnosis of the cause of their severe disorder and new genetic markers were discovered for development in the future as diagnostic tools

2) Treatment
Whole genome sequencing was validated as a tool to identify new disease mechanisms and the cause in patients with Dravet syndrome of unknown cause

3) Counselling
The study has contributed changes in recurrence risk counselling practices to more accurately inform parents of their family planning options

1.Helbig KL, Lauerer RJ, Bahr JC, Souza IA, et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. Am J Hum Genet. 2019; 104: 562. doi: 10.1016/j.ajhg.2019.02.015.

2.Myers KA, McMahon JM, Mandelstam SA, Mackay MT, Kalnins RM, Leventer RJ, Scheffer IE. Fatal cerebral edema with status epilepticus in children with Dravet syndrome: Report of 5 Cases. Pediatrics. 2017; 139: pii: e20161933. doi: 10.1542/peds.2016-1933.

3.Carvill GL, Engel KL, Ramamurthy A, Cochran JN, Roovers J et al. Aberrant inclusion of a poison exon causes Dravet syndrome and related SCN1A-associated genetic epilepsies. Am J Hum Genet. 2018; 103 :1022-1029. doi: 10.1016/j.ajhg.2018.10.023.

4.Bar C…Scheffer IE, Kabashi E, Nabbout R. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature. Hum Mutat. 2020; 41: 69-80. doi: 10.1002/humu.23915.

5.Berecki G, Bryson A, Terhag J, Maljevic S, Gazina EV, Hill SL, Petrou S. SCN1A gain of function in early infantile encephalopathy. Ann Neurol. 2019; 85: 514-525. doi: 10.1002/ana.25438.

6.Berecki G, Howell KB, Deerasooriya YH, Cilio MR, Oliva MK, Kaplan D, Scheffer IE, Berkovic SF, Petrou S. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy. Proc Natl Acad Sci USA. 2018; 115: E5516-E5525. doi: 10.1073/pnas.1800077115.

7.Li M, Maljevic S, Phillips AM, Petrovski S, Hildebrand MS, Burgess R, Mount T, Zara F, Striano P, Schubert J, Thiele H, Nürnberg P, Wong M, Weisenberg JL, Thio LL, Lerche H, Scheffer IE, Berkovic SF, Petrou S, Reid CA. Gain-of-function HCN2 variants in genetic epilepsy. Hum Mutat. 2018; 39:202-209. doi: 10.1002/humu.23357.

8.McTague A, Nair U, Malhotra S, Meyer E, Trump N, Gazina EV, Papandreou A, Ngoh A, Ackermann S, Ambegaonkar G, Appleton R, Desurkar A, Eltze C, Kneen R, Kumar AV, Lascelles K, Montgomery T, Ramesh V, Samanta R, Scott RH, Tan J, Whitehouse W, Poduri A, Scheffer IE, Chong WKK, Cross JH, Topf M, Petrou S, Kurian MA. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology. 2018; 90: e55-e66. doi: 10.1212/WNL.0000000000004762.