Pathophysiology of<unk>  seizures has been widely studied in animal models but is not fully decoded to date. There is however solid evidence for the involvement of bilateral cortical and subcortical networks which are part of the default state system. Pathophysiology when genetic mutations are present is further discussed below. Particularly in the Han Chinese population, there is an association between mutations in the calcium channel, voltage-dependent, T type, alpha 1H subunit (CACNA1H), and<unk> . These mutations cause increased channel activity and associated with increased neuronal excitability. Seizures are believed to originate in the thalamus, where there is an abundance of T-type calcium channels such as those encoded by the CACNA1H gene (12). In a European study for CACNA1H associated with<unk> , 20 mutations have been identified. 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<unk>  and CACNA1H mutations. Many of the CACNA1H mutations have a measurable effect on channel kinetics and especially on activation time constant and voltage dependence, on deactivation time constant, and on inactivation time constant and voltage dependence (summarized in Table 1) leading either to neuronal excitability or hyperexcitability. However, these predictions result from mathematical modeling and may differ from what occurs in neurons (in vivo) where other proteins, some of which may interact with CACNA1H, are present. Along with mutations in the CACNA1H gene, two mutations in gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), the gene encoding a GABAA receptor gamma subunit, are also associated with a<unk> -like phenotype that also overlaps with generalized epilepsy with febrile seizures plus type-3. The first of these, R43Q, abolishes benzodiazepine potentiation of gamma-aminobutyric acid induced currents.The second associated mutation, C588T, has not been further characterized. +Table 1. Summary of mutations in CACNA1H associated with<unk>  Mutation Region Activation Deactivation Inactivation Excitability Prediction References V50 Tau V50 Tau F161L D1S2-3 Unchanged* Unchanged Depolarized Accelerated Unchanged Hypoexcitable ,, E282K D1S5-6 Hyperpolarized Unchanged Unchanged Unchanged Unchanged Hypoexcitable ,, P314S D1-2 ? ? ? ? ? ? C456S D1-2 Hyperpolarized Accelerated Unchanged Unchanged Unchanged Hyperexcitable ,, A480T D1-2 ? Unchanged ? ? Unchanged ? , P492S D1-2 ? ? ? ? ? ? , G499S D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged , P618L D1-2 ? Accelerated ? ? Accelerated ? , V621fsX654 D1-2 ? ? ? ? ? ? P648L D1-2 Unchanged Unchanged Unchanged Depolarized Slowed Hyperexcitable , R744Q D1-2 Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged , A748V D1-2 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged , G755D D1-2 ? Unchanged ? ? Accelerated ? , G773D D1-2 Depolarized Slowed Slowed Depolarized Slowed Hyperexcitable , G784S D1-2 Unchanged Slowed Unchanged Unchanged Unchanged Unchanged , R788C D1-2 Depolarized Slowed Slowed Unchanged Slowed Hyperexcitable , G773D + R788C D1-2 Unchanged Unchanged Slowed Unchanged Unchanged Hyperexcitable V831M D2S2 Unchanged Hyperpolarized Slowed Depolarized Slowed Hypoexcitable ,, G848S D2S2 Unchanged Unchanged Slowed Unchanged Unchanged Unchanged , D1463N D2S5-6 Unchanged Accelerated Unchanged Unchanged Unchanged Unchanged ,, * Depending on experimental paradigm
Childhood absence epilepsy
Benign infantile epilepsy
Benign familial infantile epilepsy
Benign familial neonatal seizures
Northern epilepsy syndrome
Musicogenic epilepsy
Juvenile myoclonic epilepsy
Temporal lobe epilepsy