Helbig KL, Lauerer RJ, Bahr JC, et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias [published online October 18, 2018]. Am J Hum Genet. https://doi.org/10.1016/j.ajhg.2018.09.006.
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α 1-subunit of the voltage-gated Ca V2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca V2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
A large team of international researchers has identified a gene that causes developmental and epileptic encephalopathy (DEE), and the findings may lead to medical therapies to treat children with this severe and intractable pediatric epilepsy syndrome.
DEEs are severe neurodevelopmental disorders that often begin in infancy or early childhood. They feature refractory seizures, high levels of epileptiform activity on electroencephalography, severe hypotonia, and profound developmental impairment or even developmental regression. They often are associated with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early mortality.
In their study, published on October 18, 2018, in the American Journal of Human Genetics,1 the investigators identified a number of spontaneous pathogenic mutations in the calcium voltage-gated channel subunit α1 E gene (CACNA1E) in 30 participants with DEE. Participants with CACNA1E variants had disruptions in these brain-cell calcium channel, causing the channel to activate too easily or to inactivate too slowly, and giving rise to epilepsy.
Administering the antiseizure drug topiramate, which blocks these calcium channels, led to freedom from seizures in 5 of the study participants.
“Even though variants in this gene were only just discovered to cause disease, we already have a good understanding of how changes in the gene’s associated protein affect brain function—causing neural overactivity in epilepsy,” said first author Katherine L. Helbig, MS, CGC, a research genetic counselor in the Neurogenetics Program in the Division of Neurology at Children’s Hospital of Philadelphia. “Furthermore, although much follow-up research remains to be done, we found that there is a possibility that specific anti-seizure medications could reduce this overactivity in some patients.”