Childhood absence epilepsy
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Childhood absence epilepsy (CAE) is a subtype of idiopathic generalized epilepsy and is characterized by brief impairment of consciousness (absence seizure), typically without convulsions. The seizures appear between ages 3 and 12 and can occur multiple times per day. Patients are otherwise normal with no physical or neurological defects. Mutations in CACNA1H yield susceptibility for CAE and some mutations in GABRG2 yield susceptibility to CAE with febrile convulsions.1,2
Signs and symptoms
CAE is typified by absence seizures that are the first seizure type in the patient and begin between ages 3 and 12. These seizures occur numerous times per day and are associated with 3Hz spike-and-wave discharges bilaterally.
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.3 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.4,5 The second associated mutation, C588T has not been further characterized.
|G773D + R788C||D1-2||Unchanged||Unchanged||Slowed||Unchanged||Unchanged||Hyperexcitable||6|
|Depending on experimental paradigm|
See the corresponding section in the main epilepsy article.
The primary goal of treatment of childhood absence epilepsy is to prevent accidental injuries that may occur during seizures. For those with frequent seizures the goal of treatment includes preventing the seizures from interfering with learning at school and other activities of daily life.
The goal of treatment with medications for absence seizures is to accomplish the goals above, by eliminating or reducing the frequency of the absence seizures, without causing side-effects more serious than the epilepsy itself.
Certain anticonvulsant drugs are used to minimize the number of seizures. Absence seizures appear to respond well to valproic acid (trade name: Depakote), ethosuximide (trade name: Zarontin), and lamotrigine (trade name: Lamictal). Each of these medications has potential side effects, some of them serious. While the most serious side effects are uncommon, a better understanding of the risks and benefits of each of these medications would benefit many parents and guardians who must consent to treatment for their children.
For childhood absence epilepsy, there is insufficient evidence to know which, if any, of the available medications is best, i.e., having the best combination of safety and efficacy.  Nor is it known how long medication must be continued before a trial off medication should be conducted to determine if the individual has outgrown the absence seizures, as children so often do.
To date, there have been no published results of any large, double-blind, placebo-controlled studies comparing the efficacy and safety of these or any other medications for absence seizures.
The U.S. government is currently sponsoring such a study.  The purpose of this study is to determine the best initial treatment for childhood absence epilepsy from among valproic acid, ethosuximide and lamotrigine. In addition, the researchers hope to develop methods that may be used in the future to help choose the best medicine for each child diagnosed with absence seizures. The 5-year study began in 2004, and is expected to involve more than 400 children.
Also included in the study will be pharmacokinetics and pharmacogenetics research. Pharmacokinetics is the study of how the body absorbs, distributes, metabolizes, and excretes drugs. Pharmacogenetics is the study of genetic determinants of the response to drugs. Knowledge gained from this study may lead to individualized treatment for children with absence seizures.
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.
- Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo W, Qiang B, Chan P, Shen Y, Wu X (2003). "Association between genetic variation of CACNA1H and childhood absence epilepsy.". Ann Neurol 54 (2): 239-43. PMID 12891677.
- Khosravani H, Altier C, Simms B, Hamming K, Snutch T, Mezeyova J, McRory J, Zamponi G (2004). "Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy.". J Biol Chem 279 (11): 9681-4. PMID 14729682.
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- Wallace R, Marini C, Petrou S, Harkin L, Bowser D, Panchal R, Williams D, Sutherland G, Mulley J, Scheffer I, Berkovic S (2001). "Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.". Nat Genet 28 (1): 49-52. PMID 11326275.
- Marini C, Harkin L, Wallace R, Mulley J, Scheffer I, Berkovic S (2003). "Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor mutation.". Brain 126 (Pt 1): 230-40. PMID 12477709.
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- Liang J, Zhang Y, Wang J, Pan H, Wu H, Xu K, Liu X, Jiang Y, Shen Y, Wu X (2006). "New variants in the CACNA1H gene identified in childhood absence epilepsy.". Neurosci Lett 406 (1-2): 27-32. PMID 16905256.
- Heron S, Phillips H, Mulley J, Mazarib A, Neufeld M, Berkovic S, Scheffer I (2004). "Genetic variation of CACNA1H in idiopathic generalized epilepsy.". Ann Neurol 55 (4): 595-6. PMID 15048902.
- Khosravani H, Bladen C, Parker D, Snutch T, McRory J, Zamponi G (2005). "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy.". Ann Neurol 57 (5): 745-9. PMID 15852375.
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