Childhood absence epilepsy
Childhood absence epilepsy (CAE), also known as pyknolepsy, is an idiopathic generalized epilepsy which occurs in otherwise normal children. The age of onset is between 4–10 years with peak age between 5–7 years. Children have absence seizures which although brief (~4–20 seconds), they occur frequently, sometimes in the hundreds per day. The absence seizures of CAE involve abrupt and severe impairment of consciousness. Mild automatisms are frequent, but major motor involvement early in the course excludes this diagnosis. The EEG demonstrates characteristic "typical 3Hz spike-wave" discharges. Prognosis is excellent in well-defined cases of CAE with most patients "growing out" of their epilepsy.
CAE is a complex polygenic disorder. Particularly in the Han Chinese population there is association between mutations in CACNA1H and CAE. These mutations cause increased channel activity and associated 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 CACNA1H.
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 GABAA 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.
Table 1. Summary of mutations in CACNA1H associated with childhood absence epilepsy 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
Diagnosis is made upon history of absence seizures during early childhood and the observation of ~3 Hz spike-and-wave discharges on an EEG.
Childhood absence epilepsy is a fairly common disorder with a prevalence of 1 in 1000 people. Few of these people will likely have mutations in CACNA1H or GABRG2 as the prevalence of those in the studies presented is 10% or less.
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