Childhood Absence Epilepsy

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Retrieved

2021-01-18

Source

Wikipedia

Trials

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Genes

CACNA1A, CACNA2D2, GABRB3, CACNA1H, JRK, KCNK9, EFHC1, HCN1, NPY, HTR7, YWHAZ, MMP9, CACNG2, NPY1R, NPY2R, GLUD1, NPY5R, GABRG2, SLC2A1, GABRA1, CACNA1G, NIPA2, ECA1, PVALB, GJA8, GABRA5, GABBR1, CAV3, SCN8A, CACNA1I, CLCN2, SREBF1, SLC1A2, THBS1, TCOF1, SLC6A1, UBE3A, KHDRBS3, SMC1A, LOH19CR1, CACNG3, SCN1A, TRAK1, CNTNAP2, NLE1, PCNX2, MAGT1, PIGO, DBA2, LGI4, BRAT1, SCN1B, ALPI, RPS19, RORB, PDIA3, GRM4, GRM1, GRIA4, GRIA2, GFAP, GABRD, GABRA6, ESR1, CLN8, EGR1, DYRK1A, CHRNA7, CD47, CANX, HSP90AB1, HTR1A, HTR2A, NOTCH1, RCN2, PLCB4, PI3, ABCB1, OPRM1, ALPP, MEF2C, IAPP, MECP2, KCNQ3, KCNJ10, INHA, IL6, IGHE, MIR597

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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.

Signs and symptoms

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.

**Table 1.** Summary of mutations in CACNA1H associated with childhood absence epilepsy
Mutation	Region	Activation		Deactivation	Inactivation		Excitability Prediction	References
Mutation	Region	V₅₀	Tau	Deactivation	V₅₀	Tau	Excitability Prediction	References
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

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

Management

Epidemiology

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.