Juvenile myoclonic epilepsy - CACNB4, CLCN2, EFHC1, GABRA1 and GABRD genes

Juvenile myoclonic epilepsy is an alteration characterized by epilepsy. In affected people, this alteration manifests itself in childhood or adolescence, usually between 12 and 18 years, and lasts until adulthood. The most common type of seizures is the myoclonic crisis, which causes rapid and uncontrollable muscle contractions. In addition, affected individuals may also present generalized tonic-clonic seizures, known as epileptic seizures, which result in muscle stiffness, seizures and loss of consciousness. Sometimes, affected individuals have loss of consciousness for a short period of time. In general, people with juvenile myoclonic epilepsy develop characteristic myoclonic seizures in adolescence and, a few years later, develop generalized tonic-clonic seizures. Although seizures can occur at any time, they occur most often in the morning, shortly after awakening. Seizures can be caused by lack of sleep, extreme tiredness or alcohol consumption.

The genetics of juvenile myoclonic epilepsy are complex and not completely clear. Mutations in one of several genes can cause or increase susceptibility to this disease. The best-studied genes are the GABRA1 gene (gamma-aminobutyric acid type A receptor alpha1 subunit) and the EFHC1 gene (EF-hand domain containing 1). Mutations in the CACNB4 (calcium voltage-gated channel auxiliary subunit beta 4), CLCN2 (chloride voltage-gated channel 2) and GABRD (gamma-aminobutyric acid type A receptor delta subunit) genes have also been identified in people with juvenile myoclonic epilepsy. In many people with juvenile myoclonic epilepsy, no mutations have been identified in these genes. Changes in other unidentified genes are likely to be involved in the development of this condition.

The GABRA1 gene (gamma-aminobutyric acid type A receptor alpha1 subunit), located on the long arm of chromosome 5 (5q34) and the GABRD gene (gamma-aminobutyric acid type A receptor delta subunit), located on the short arm of chromosome 1 (1p36.3), encode the alpha (α1) and delta subunits of the GABAA receptor protein, respectively. GABAA receptors are composed of different combinations of five protein subunits, each encoded from a different gene. These subunits form a pore in the cell membrane through which the chloride ions can flow. A neurotransmitter called gamma amino butyric acid (GABA) binds to GABAA receptors. Once GABA is bound, the pore formed by the subunits is opened and the chloride ions flow through the cell membrane. After infancy, chloride ions flow into the cell through the open pore, creating an environment in the cell that inhibits signaling between neurons. The main function of GABA in children and adults is to prevent the brain from being overloaded with too many signals. In contrast, in newborns and infants, chloride ions flow outside the cell when the pore is opened, creating an environment that allows signaling between neurons.

A mutation in the GABRA1 gene has been identified in at least one family with juvenile myoclonic epilepsy. The associated mutation replaces the amino acid alanine with the amino acid asparagine at position 322 (Ala322Asp or A322D), which leads to the coding of an abnormal α1 subunit that reduces the function of the GABA receptor. As a consequence, GABA receptors that contain the abnormal subunit decompose before they reach the cell membrane. Altered receptors can also interfere with normal receptors within the cell, leading to further loss of normal receptors. Due to the reduction of the function of the GABAA receptor, the signaling between the neurons is not regulated, which can lead to the overstimulation of the neurons. It is likely that overstimulation of certain neurons in the brain triggers abnormal brain activity associated with seizures.

The EFHC1 gene (EF-hand domain containing 1), located on the short arm of chromosome 6 (6p12.3), encodes the protein with domain EF 1 (EFHC1). The EFHC1 protein interacts with another protein that acts as a calcium channel, allowing calcium ions to pass through the cell membrane. The movement of these ions is critical for normal signaling between neurons in the brain and other parts of the nervous system. The role of the EFHC1 protein is not well understood, although it is believed to help regulate calcium homeostasis. Studies also show that the EFHC1 protein can stimulate apoptosis. Mutations in the EFHC1 gene have been identified in a small number of people with juvenile myoclonic epilepsy. Most of the genetic mutations associated with juvenile myoclonic epilepsy substitute amino acids in the EFHC1 protein, which alters the function of the protein. Although it is not clear how genetic mutations EFHC1 give rise to juvenile myoclonic epilepsy, it is likely that the decrease in protein function reduces apoptosis, which alters calcium homeostasis. Taken together, these changes can lead to excess stimulation of the neurons, causing seizures typical of juvenile myoclonic epilepsy.

The CACNB4 gene (calcium voltage-gated channel auxiliary subunit beta 4), located on the long arm of chromosome 2 (2q23.3), belongs to the family of genes that encode the structure of calcium channels. Specifically, this gene encodes the β4 regulatory subunit. This subunit is more associated with calcium channels in the brain, particularly in the cerebellum. In the brain, calcium channels play an essential role in the communication between neurons. These channels help control the release of neurotransmitters. It is believed that calcium channels are also involved in the survival of neurons and the plasticity of these cells. Mutations in the CACNB4 gene have been associated with epilepsy in a small number of families. One of these mutations, Arg482Ter or R482X, creates a stop signal at position 482 of the β4 subunit. This mutation results in a β4 subunit in which a critical region for interaction with the α1 subunit is absent. Calcium channels with an altered β4 subunit close more rapidly than usual, which reduces the flow of calcium ions into the cell. It is likely that impaired calcium ion transport disrupts communication between nerve cells. Another mutation in the CACNB4 gene, Cys104Phe, seems to cause epilepsy in at least one family.

The CLCN2 (chloride voltage-gated channel 2) gene, located on the long arm of chromosome 3 (3q27.1), encodes a transmembrane protein that maintains homeostasis of chloride ions in various cells. Defects in this gene can be a cause of certain types of epilepsy.

The inheritance pattern of juvenile myoclonic epilepsy is not completely known. When the disease is due to mutations in the GABRA1 gene, it is inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient for the disease to be expressed. When the disease is due to mutations in the EFHC1 gene, the inheritance pattern is unknown. Although juvenile myoclonic epilepsy often occurs in families, many cases occur in people with no family history of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Juvenile Myoclonic Epilepsy, by means of the complete PCR amplification of the exons of the CACNB4, CLCN2, EFHC1, GABRA1 and GABRD genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).