Childhood Absence Epilepsy - Pathophysiology

Pathophysiology

There are currently 20 mutations in CACNA1H associated with CAE. These mutations are likely not wholly causative and should instead be thought of as giving susceptibility. This is particularly true since some groups have found no connection between CAE and CACNA1H mutations. Many of the CACNA1H mutations have a measurable effect on channel kinetics, including activation time constant and voltage dependence, deactivation time constant, and inactivation time constant and voltage dependence (summarized in Table 1). Many of these mutations should lead to neuronal excitability, though others may lead to hypoexcitability. These predictions are due to mathematical modeling and may differ from what will occur in real neurons where other proteins, some of which may interact with CACNA1H, are present.

Along with mutations in CACNA1H, two mutations in the gene encoding a GABA_A receptor γ subunit are also associated with a CAE like phenotype that also overlaps with generalized epilepsy with febrile seizures plus type-3. The first of these, R43Q, abolishes benzodiazepine potentiation of GABA induced currents. The second associated mutation, C588T has not been further characterized.