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]

Contents 1 Signs and symptoms 2 Causes 3 Pathophysiology 4 Diagnosis 5 Treatment/Management 6 Epidemiology 7 References 8 Footnotes 9 See also

[edit] 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.

[edit] Causes

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.

[edit] 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.^[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 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.^[4][5] 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	[1],[2],[6]
E282K	D1S5-6	Hyperpolarized	Unchanged	Unchanged	Unchanged	Unchanged	Hypoexcitable	[1],[2],[6]
P314S	D1-2	?	?	?	?	?	?	[7]
C456S	D1-2	Hyperpolarized	Accelerated	Unchanged	Unchanged	Unchanged	Hyperexcitable	[1],[2],[6]
A480T	D1-2	?	Unchanged	?	?	Unchanged	?	[8],[9]
P492S	D1-2	?	?	?	?	?	?	[7],[7]
G499S	D1-2	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	[1],[6]
P618L	D1-2	?	Accelerated	?	?	Accelerated	?	[8],[9]
V621fsX654	D1-2	?	?	?	?	?	?	[8]
P648L	D1-2	Unchanged	Unchanged	Unchanged	Depolarized	Slowed	Hyperexcitable	[1],[6]
R744Q	D1-2	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	[1],[6]
A748V	D1-2	Unchanged	Accelerated	Unchanged	Unchanged	Unchanged	Unchanged	[1],[6]
G755D	D1-2	?	Unchanged	?	?	Accelerated	?	[8],[9]
G773D	D1-2	Depolarized	Slowed	Slowed	Depolarized	Slowed	Hyperexcitable	[1],[6]
G784S	D1-2	Unchanged	Slowed	Unchanged	Unchanged	Unchanged	Unchanged	[1],[6]
R788C	D1-2	Depolarized	Slowed	Slowed	Unchanged	Slowed	Hyperexcitable	[6],[7]
G773D + R788C	D1-2	Unchanged	Unchanged	Slowed	Unchanged	Unchanged	Hyperexcitable	[6]
V831M	D2S2	Unchanged	Hyperpolarized	Slowed	Depolarized	Slowed	Hypoexcitable	[1],[2],[6]
G848S	D2S2	Unchanged	Unchanged	Slowed	Unchanged	Unchanged	Unchanged	[1],[6]
D1463N	D2S5-6	Unchanged	Accelerated	Unchanged	Unchanged	Unchanged	Unchanged	[1],[2],[6]
*	Depending on experimental paradigm

[edit] Diagnosis

Diagnosis is made upon history of absence seizures during early childhood and the observation of ~3Hz spike-and-wave discharges on an EEG.

[edit] Treatment/Management

See the corresponding section in the main epilepsy article.

[edit] Epidemiology

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.

[edit] References

• Perez-Reyes E (2006). "Molecular characterization of T-type calcium channels.". Cell Calcium 40 (2): 89-96. PMID 16759699.

[edit] Footnotes

1. ^ ^{a b c d e f g h i j k l m} 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.
2. ^ ^{a b c d e f} 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.
3. ^ Chioza B, Everett K, Aschauer H, Brouwer O, Callenbach P, Covanis A, Dulac O, Durner M, Eeg-Olofsson O, Feucht M, Friis M, Heils A, Kjeldsen M, Larsson K, Lehesjoki A, Nabbout R, Olsson I, Sander T, Sirén A, Robinson R, Rees M, Gardiner R (2006). "Evaluation of CACNA1H in European patients with childhood absence epilepsy.". Epilepsy Res 69 (2): 177-81. PMID 16504478.
4. ^ 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.
5. ^ 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.
6. ^ ^{a b c d e f g h i j k l m n} Vitko I, Chen Y, Arias J, Shen Y, Wu X, Perez-Reyes E (2005). "Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel.". J Neurosci 25 (19): 4844-55. PMID 15888660.
7. ^ ^a b c d 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.
8. ^ ^a b c d 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.
9. ^ ^a b c 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.

[edit] See also

• Generalized epilepsy with febrile seizures plus
• Absence seizure
• Epilepsy
• Calcium channel