Documentaries: Both Informing and Entertaining New Zealanders

Interview by Laurence Weinstein of William De Friez and Veronica McCarthy, owners of Raconteur Productions in New Zealand. William (“Bill”) De Friez and Veronica (“Ronni”) McCarthy own and operate Raconteur Film and Television Productions located in downtown Christchurch. Bill serves as part-time director; his full-time position is faculty lecturer in the Film Department of the University of Canterbury. Ronni is the full-time producer for their small business operation that completes an average of three documentaries per year as well as a network children’s series and other special projects. She won the prestigious Winston Churchill Fellowship in 1995 to study children’s television outside of New Zealand

Dr. Laurence Weinstein Editor in Chief

From the “Practitioner’s Corner Musings of a Serial Entrepreneur—Reconciling Theory with Practic

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

International audienceDevelopmental 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 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 four 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 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