Childhood absence epilepsy (CAE) – CACNA1H, GABRA1, GABRB3, GABRG2 and JRK genes

Childhood epilepsy with absences (CAE) is a disease characterized by episodes of epilepsy in which affected individuals suffer brief episodes of altered consciousness or episodes of absence.

This process usually begins between 3 and 8 years of age. During seizures, children are not aware of or respond to people or the activities that surround them. Seizures usually last several seconds and occur frequently, up to 200 times each day. In some cases, affected individuals have febrile seizures before developing childhood epilepsy with absences. In most affected people, absence crises disappear in adolescence.

It is believed that this process is due to multiple genetic changes or a combination of genetic and environmental factors. Most of the genetic changes associated with the disease are rare, having been found in only a small number of affected individuals. So far, mutations have been described in the CACNA1H (calcium voltage-gated channel subunit alpha1 H), GABRA1 (gamma-aminobutyric acid type A receptor alpha1 subunit), GABRB3 (gamma-aminobutyric acid type A receptor beta3 subunit), GABRG2 (gamma-aminobutyric acid type A receptor gamma2 subunit) and JRK (Jrk helix-turn-helix protein) genes.

Several of the genes associated with the disease, including the GABRA1 gene, located on the long arm of chromosome 5 (5q34); GABRB3 gene, located on the long arm of chromosome 15 (15q12); and GABRG2 gene, located on the long arm of chromosome 5 (5q34), encode subunits of the GABAA receptor protein. The GABAA receptor acts as a channel that allows chloride ions to pass through the cell membrane. The influx of chloride ions into the neurons creates an environment that inhibits signaling between neurons and prevents the brain from being overloaded with too many signals. Mutations in the GABAA receptor subunit genes result in the synthesis of altered protein subunits that cannot form functional receptors, so there are fewer GABAA receptors available. As a result, neurons are overloaded with signals. It is thought that overstimulation of certain neurons in the brain triggers the abnormal brain activity associated with seizures.

In addition to these genes, mutations have been identified in the CACNA1H gene, located on the short arm of chromosome 16 (16p13.3), which encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channels. Calcium channels carry calcium ions to cells. These channels help control the release of neurotransmitters. Mutations that give rise to hyperactive calcium channels cause overstimulation of certain neurons, triggering seizures.

This disease seems to be a complex disease without a single genetic cause, so it does not have a direct inheritance pattern. When associated with mutations in the GABAA receptor or calcium channel genes, it appears to follow an autosomal dominant inheritance pattern, meaning that one copy of the altered gene in each cell is sufficient to increase the likelihood of developing the disease. Some people who have the altered gene never develop the disease, a situation known as reduced penetrance.

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with childhood epilepsy with absences, by complete PCR amplification of the exons of the CACNA1H, GABRA1, GABRB3, GABRG2 and JRK genes, respectively, and their subsequent sequencing .

Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).