Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Episodic ataxia types 1, 2, 5 and 6 (Episodic ataxia types 1, 2, 5 and 6) - Genes KCNA1, CACNA1A, CACNB4 and SLC1A3.

Episodic ataxias are a group of diseases affecting the central nervous system and cause engine problems characterized by recurrent episodes of motor incoordination and imbalance. During episodes, many of those affected manifest dizziness, nausea, vomiting, headaches, blurred or double vision, dyslexia and tinnitus. Sometimes during episodes convulsions, muscle weakness and hemiplegia may occur. These episodes can start anytime, from childhood to adulthood, and can be triggered by environmental factors, emotional stress, caffeine, alcohol, certain medications, physical activity and disease. The frequency of episodes can vary from several per day to one or two per year. Between episodes, some affected continue with ataxia, can worsen over time and manifest nystagmus.

Have been described at least seven types (1 to 7) of episodic ataxia, differentiated by the set of signs and symptoms displayed affected, the age of onset, duration of attacks and genetic causes.

Several genes have been linked to these processes: KCNA1, CACNA1A, CACNB4, SLC1A3. These genes encode proteins involved in ion transport through membranes of neurons, necessary for communication signals between neurons in the brain and other parts of the nervous system. Mutations in KCNA1, CACNA1A and CACNB4 genes, are responsible for types 1, 2 and 5, respectively, and mutations in the SLC1A3 gene are responsible for the type 6. In the latter type, the gene encodes a protein involved in glutamate transport. For type 3, 4 and 7 genetic alteration remains unknown.

Episodic ataxia type 1 (EA1) is due to mutations in the gene KCNA1, located on the short arm of chromosome 12 (12p13, 32). This gene belongs to a family of genes encoding proteins to form potassium channels transporting potassium ions into neurons , and play a role in the ability of cells to generate and transmit electrical signals. This gene encodes the alpha subunit of a potassium channel Kv1.1 known, found in the central nervous system. They have been described at least 20 mutations in affected persons episodic ataxia type 1 (EA1). Most of these mutations change the amino acid alpha subunit Kv1.1 channel. When these channels are missing, or are abnormal, the flow of potassium neurons is reduced. Decreasing potassium overdriven some brain neurons, altering the communication between them.

Episodic ataxia type 2 (EA2) is due to mutations in CACNA1A, located on the short arm of chromosome 19 (19p13). This gene belongs to the family of genes that encode the structure of calcium channels. These channels carry calcium atoms positive charge through the membrane. Calcium ions are involved in various cellular functions, including intercellular communication and survival of neurons. Specifically, this gene encodes the alpha subunit 1 calcium channel Cav2.1 called, which form a pore through which calcium flows. We found more than 50 mutations in this gene are responsible for episodic ataxia type 2, characterized by nystagmus. Mutations in CACNA1A reduce encoding Cav2.1 channels functional, or prevent these channels reach the cell membrane, where they are needed for transport of calcium ions. A decrease in the number of these channels reduces the total flow of calcium ions into neurons, which interrupts the release of neurotransmitters in the brain. Although changes in signaling between neurons underlie episodes of lack of coordination, it is not clear how the altered transport of calcium ions causes the disease characteristics.

Episodic ataxia type 5 (EA5), is due to mutations in the gene CACNB4, located on the long arm of chromosome 2 (2q22-q23). This gene, which belongs to the family of genes that encode the structure of the calcium channel encodes the regulatory subunit beta-4 (?4). This subunit is associated more with the calcium channels in the brain, particularly in the cerebellum. It has identified at least one mutation in a family with episodic ataxia type 5 (EA5). This mutation replaces the amino acid cysteine by amino acid at position 104 phenylalanine (Cys104Phe or C104F). It is believed that this genetic change can alter the ability ?4 subunit to interact with other proteins and somehow disrupts normal function of calcium channels in the brain.

Episodic ataxia type 6 (EA6), is due to mutations in the SLC1A3 gene, located on the short arm of chromosome 5 (5p13). This gene encodes the protein EAAT1, carrying molecules of glutamate, a neurotransmitter that enable communication between neurons. This protein is found throughout the brain, but is most abundant in the brain stem and cerebellum. Neurotransmitters, including glutamate, are released from neurons and transmit signals to other cells by binding to receptor proteins in neighboring neurons. It has been determined that one of several EAAT1 glutamate transporters compensating excess glutamate. This process is regulated carefully to ensure that the signals are transmitted accurately throughout the nervous system. The timely removal of glutamate is also necessary to prevent an accumulation of the neurotransmitter between cells, which would be toxic to neurons. It has identified at least one mutation in the SLC1A3 gene replacing the amino acid proline in the amino acid arginine position 290 (Pro290Arg). It is believed that this mutation impairs the ability of EAAT1 to remove glutamate from the space between neurons. Altered glutamate uptake may overload certain neurons in the brain, interrupting the normal communication between these cells.

These processes are autosomal dominant inheritance, which means that a single copy of the altered gene in a cell is sufficient to manifest. The process may be the result of heredity or a new mutation, with no prior history.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with ataxia types 1, 2, 5 and 6, by complete PCR amplification of the exons of KCNA1, CACNA1A, CACNB4, SLC1A3 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).