Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy

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 alpha(2)delta 2 subunit of high voltage gated calcium channels. The expression of the alpha(2)delta 2-L1040P mutant instead of alpha(2)delta 2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (Ca(V)2.2) and L (Ca(V)1.2) type calcium channels. Western blot and confocal imaging analyses showed that the alpha(2)delta 2-L1040P mutant was synthesised normally in oocyte but only the alpha(2)delta 2-WT, and not the a2d2-L1040P mutant, increased the expression of alpha(1B), the pore forming subunit of Ca(V)2.2, at the plasma membrane. The expression of alpha(2)delta 2-WT with Ca(V)2.2 increased the surface expression of alpha(1B) 2.5-3 fold and accelerated current inactivation, whereas alpha(2)delta 2-L1040P did not produce any of these effects. Conclusions L1040P mutation in the CACNA2D2 gene is associated with dysfunction of alpha(2)delta 2, 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 alpha(2)delta 2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary alpha(2)delta subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.