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Childhood absence epilepsy

Childhood absence epilepsy (CAE), also known as Pyknolepsy, 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.

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.

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.

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.

! rowspan="2" | Mutation

! rowspan="2" | Region

! colspan="2" | Activation

! rowspan="2" | Deactivation

! colspan="2" | Inactivation

! rowspan="2" | Excitability Prediction

! rowspan="2" | References

! V₅₀

! Tau

! V₅₀

! Tau

! F161L

! E282K

! P314S

! C456S

! A480T

! P492S

! G499S

! P618L

! V621fsX654

! P648L

! R744Q

! A748V

! G755D

! G773D

! G784S

! R788C

! G773D + R788C

! V831M

! G848S

! D1463N

Table 1. Summary of mutations in CACNA1H associated with childhood absence epilepsy
D1S2-3	Unchanged*	Unchanged	Depolarized	Accelerated	Unchanged	Hypoexcitable	^,^,
D1S5-6	Hyperpolarized	Unchanged	Unchanged	Unchanged	Unchanged	Hypoexcitable	^,^,
D1-2	?	?	?	?	?	?
D1-2	Hyperpolarized	Accelerated	Unchanged	Unchanged	Unchanged	Hyperexcitable	^,^,
D1-2	?	Unchanged	?	?	Unchanged	?	^,
D1-2	?	?	?	?	?	?	^,
D1-2	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	^,
D1-2	?	Accelerated	?	?	Accelerated	?	^,
D1-2	?	?	?	?	?	?
D1-2	Unchanged	Unchanged	Unchanged	Depolarized	Slowed	Hyperexcitable	^,
D1-2	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	Unchanged	^,
D1-2	Unchanged	Accelerated	Unchanged	Unchanged	Unchanged	Unchanged	^,
D1-2	?	Unchanged	?	?	Accelerated	?	^,
D1-2	Depolarized	Slowed	Slowed	Depolarized	Slowed	Hyperexcitable	^,
D1-2	Unchanged	Slowed	Unchanged	Unchanged	Unchanged	Unchanged	^,
D1-2	Depolarized	Slowed	Slowed	Unchanged	Slowed	Hyperexcitable	^,
D1-2	Unchanged	Unchanged	Slowed	Unchanged	Unchanged	Hyperexcitable
D2S2	Unchanged	Hyperpolarized	Slowed	Depolarized	Slowed	Hypoexcitable	^,^,
D2S2	Unchanged	Unchanged	Slowed	Unchanged	Unchanged	Unchanged	^,
D2S5-6	Unchanged	Accelerated	Unchanged	Unchanged	Unchanged	Unchanged	^,^,
*	Depending on experimental paradigm

Diagnosis

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

Treatment/Management

For the main article on epilepsy treatment, see main epilepsy article.
For the treatment specific to Absence seizures, see treatment of absence seizures.

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.