De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic 
Encephalopathy With Contractures, Macrocephaly, and Dyskinesias Helbig KL, 
Lauerer RJ, Bahr JC, et al. Am J Hum Genet. 2019;104(3):562. 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 electroencephalogram (EEG), and 
developmental impairment or regression. CACNA1E is highly expressed in the 
central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 
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 4 S6 segments, 
which form the presumed CaV2.3 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 
antiepileptic 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.