CURE Grantee Dr. Gemma Carvill has identified a new cause of epilepsy: a mutation in the gene CUX2. Dr. Carvill’s discovery was recently published in the Annals of Neurology.
The discovery provides an important advance in our understanding of the causes of a class of severe childhood epilepsies. This class includes childhood epileptic encephalopathy, an aggressive and severe group of treatment-resistant epilepsy disorders in which children can have profound cognitive and neurological deficits.[2,3]
Dr. Carvill began her research into the ways specific genetic mutations lead to childhood epileptic encephalopathy in 2015 as the result of a 1-year CURE Taking Flight Award. This award program encourages young investigators to conduct independent research which could lead to a cure for epilepsy. When Dr. Carvill recieved the CURE Taking Flight Award, she was a Postdoctoral Fellow at the University of Washington.
Dr. Carvill studied the ways genetic mutations lead to epilepsy. Her initial findings suggested that mutations in a class of genes important in determining the structure of DNA could impact several genes involved in epilepsy, making this class of genes a potential target of future epilepsy therapy development.
Since receiving her CURE award, Dr. Carvill’s career has certainly “taken flight” – she is now Assistant Professor of Neurology and Pharmacology at Northwestern University. Still, Dr. Carvill has remained committed to her quest to understand the genetic mechanisms behind severe childhood epilepsy. In her latest study, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital, located in France, to identify de novo mutations in the gene CUX2 as a new cause of epilepsy. De novo mutations are changes present only in the affected patient and not in their healthy parents. CUX2 is important in binding DNA and promoting the expression of certain target genes. Mutations in CUX2 cause errors in this process that can lead to epilepsy.
Dr. Carvill’s report details her international study of 9 patients aged 6 months to 21 years who first began having seizures early in life. To identify the mutation in the CUX2 gene, Dr. Carvill and her team used, among other techniques, a test called whole exome sequencing. This test analyzes a person’s genes to identify changes in their DNA. All 9 patients had the same CUX2 mutation. The team found that the majority of these patients had severe treatment-resistant epilepsy that started early in life, severe intellectual disability, and did not have speech appropriate for their age.
Besides finding an important genetic cause of severe childhood epilepsy, which can now be targeted for the development of therapeutic interventions, Dr. Carvill’s collaboration with Dr. Lesca highlights the importance of international efforts to identify new genes important in epilepsy. As Dr. Carvill notes, these genetic mutations are very rare and therefore collaborative efforts with multiple patient populations make it more likely that a rare genetic mutation can be identified and studied.
In the future, Dr. Carvill plans to further explore the genetic mechanisms behind these devastating childhood epilepsies. Her goal, which we at CURE share, is that treatments and cures can be found for all of the amazing children affected by epilepsy and their wonderful families, too.
 Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol2018; 6 [Epub ahead of print]
 Cross H and Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013; 111:619-626.
 Jehi L, Wylie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome. Epilepsia 2015; 56(10):1486-1489.