CACNA1E encodes the alpha-1E subunit of voltage-gated CaV2.3 calcium channels, which mediate R-type calcium currents essential for synaptic transmission in the central nervous system 1. The protein functions as a high voltage-activated calcium channel that conducts calcium ions into excitable cells, playing critical roles in neurotransmitter release and neuronal excitability 1. Mechanistically, CACNA1E variants cause disease primarily through gain-of-function effects, including facilitated voltage-dependent activation, slowed inactivation, and increased current density, leading to enhanced calcium influx 1. These functional alterations cluster predominantly within the cytoplasmic ends of S6 segments that form the channel activation gate 1. CACNA1E is strongly associated with developmental and epileptic encephalopathy 69, characterized by refractory infantile-onset seizures, severe hypotonia, profound developmental impairment, congenital contractures, macrocephaly, and hyperkinetic movement disorders 1. The gene has also been implicated in intellectual disability/global developmental delay, with gain-of-function variants typically associated with more severe phenotypes 2. Additionally, CACNA1E was identified as a risk locus in post-traumatic stress disorder, classified among neurotransmitter and ion channel synaptic modulators 3. Clinically, some patients achieve seizure control with topiramate, which blocks R-type calcium channels, suggesting targeted therapeutic potential 1.