Background Early infantile epileptic encephalopathies usually manifest as severely impaired cognitive and motor development and often result in a devastating permanent global developmental delay and intellectual disability. A large set of genes has been implicated in the aetiology of this heterogeneous group of disorders. Among these, the ion channelopathies play a prominent role. In this study, we investigated the genetic cause of infantile epilepsy in three affected siblings.

Methods and results Homozygosity mapping in DNA samples followed by exome analysis in one of the patients resulted in the identification of a homozygous mutation, p.L1040P, in the CACNA2D2 gene. This gene encodes the auxiliary α₂δ2 subunit of high voltage gated calcium channels. The expression of the α₂δ2-L1040P mutant instead of α₂δ2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (Ca_V2.2) and L (Ca_V1.2) type calcium channels. Western blot and confocal imaging analyses showed that the α₂δ2-L1040P mutant was synthesised normally in oocyte but only the α₂δ2-WT, and not the α₂δ2-L1040P mutant, increased the expression of α_1B, the pore forming subunit of Ca_V2.2, at the plasma membrane. The expression of α₂δ2-WT with Ca_V2.2 increased the surface expression of α_1B 2.5–3 fold and accelerated current inactivation, whereas α₂δ2-L1040P did not produce any of these effects.

Conclusions L1040P mutation in the CACNA2D2 gene is associated with dysfunction of α₂δ2, resulting in reduced current density and slow inactivation in neuronal calcium channels. The prolonged calcium entry during depolarisation and changes in surface density of calcium channels caused by deficient α₂δ2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary α₂δ subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.