Episodic ataxia is a group of related conditions that affect the nervous system and cause problems with movement and coordination. People with episodic ataxia have episodes of poor coordination and balance (ataxia). During these episodes, many people also experience dizziness (vertigo), nausea and vomiting, migraines, blurred or double vision, slurred speech, and ringing in the ears (tinnitus). Seizures, muscle weakness, and paralysis that affect one side of the body (hemiplegia) may also occur during these episodes.

Additionally, a muscle abnormality called myokymia or an eye abnormality called nystagmus can occur during or between episodes. Myokymia causes muscle cramping; stiffness; or continuous, fine muscle twitching that appears as rippling under the skin. Nystagmus refers to rapid, involuntary eye movements.

Episodes of ataxia and other symptoms can begin anytime from early childhood to adulthood. They can be triggered by environmental factors such as stress, caffeine, alcohol, certain medications, physical activity, and illness. The duration of episodes may vary from seconds to days, and the frequency ranges from several episodes per day to one or two every few months. Between episodes, affected individuals may have no signs or symptoms. However, some continue to experience ataxia, which may worsen over time.

Some children with episodic ataxia have delayed development of speech or motor skills, such as standing and walking. They may also have learning difficulties.

Researchers have identified at least 11 types of episodic ataxia, distinguished by their pattern of signs and symptoms, age of onset, length of episodes, and genetic cause.

Episodic ataxia can be caused by variants (also called mutations) in several genes that play important roles in the nervous system. Several of the genes provide instructions for making proteins that are involved in the transport of charged atoms (ions) across cell membranes. The protein produced from the KCNA1 gene transports potassium ions, and the protein produced from the CACNA1A gene transports calcium ions. The movement of these ions is critical for normal signaling between nerve cells (neurons) in the brain and other parts of the nervous system. Variants in the KCNA1 and CACNA1A genes cause episodic ataxia types 1 and 2, respectively.

Variants in the SLC1A3 gene cause episodic ataxia type 6. This gene provides instructions for making a protein that transports chloride ions across cell membranes. The movement of chloride ions is thought to help maintain certain cellular conditions so the cells can survive and function. The protein also transports a brain chemical (neurotransmitter) called glutamate. Neurotransmitters allow neurons to communicate by relaying chemical signals from one neuron to another.

Researchers believe that variants in the KCNA1, CACNA1A, and SLC1A3 genes alter the transport of ions in the brain. Changes in ion transport may cause certain neurons to become overexcited, disrupting normal communication between these cells. Although episodes of ataxia are caused by changes in the brain's chemical signals, it is unclear how variants in these genes cause the specific features of the disorder.

The genetic causes of other types of episodic ataxia have not been identified or are not well documented. Researchers are looking for variants in additional genes that can cause episodic ataxia.

Normal Function

The CACNA1A gene belongs to a family of genes that provide instructions for making calcium channels. These channels, which transport positively charged calcium atoms (calcium ions) across cell membranes, play a key role in a cell's ability to generate and transmit electrical signals. Calcium ions are involved in many different cellular functions, including cell-to-cell communication, the tensing of muscle fibers (muscle contraction), and the regulation of certain genes.

The CACNA1A gene provides instructions for making one part (the alpha-1 subunit) of a calcium channel called CaV2.1. This subunit forms the hole (pore) through which calcium ions can flow. CaV2.1 channels play an essential role in communication between nerve cells (neurons) in the brain. These channels are especially abundant in neurons called Purkinje cells and granule cells. These neurons are found in the part of the brain that coordinates movement (the cerebellum) .

CaV2.1 channels help control the release of neurotransmitters, which are chemicals that relay signals from one neuron to another. Researchers believe that CaV2.1 channels are also involved in the survival of neurons and the ability of these cells to change and adapt over time (plasticity).

The CACNA1A gene also provides instructions for making another protein called alpha1-ACT (α1ACT). This protein acts as a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The α1ACT protein is important for the development of neurons, especially Purkinje cells.

Near the tail end of the CACNA1A gene, a segment of three DNA building blocks (nucleotides) is repeated multiple times. This sequence, which is written as CAG, is called a triplet or trinucleotide repeat. The number of CAG repeats in this gene typically ranges from 4 to 18.

Health Conditions Related to Genetic Changes

Episodic ataxia

Many variants (also called mutations) in the CACNA1A gene have been found to cause episodic ataxia type 2 (EA2), the most common form of episodic ataxia. EA2 is associated with episodes of poor coordination and balance (ataxia) and involuntary eye movements called nystagmus.

The CACNA1A variants that cause EA2 are known as loss-of-function variants because they reduce the function of CaV2.1 channels. The changes can impair the production of functional CaV2.1 channels; prevent the channels from reaching the cell membrane, where they are needed to transport calcium ions; or reduce the flow of calcium through the channels. A decrease in the total flow of calcium ions into neurons disrupts the release of neurotransmitters in the brain. Studies show that changes in CaV2.1 channels can disrupt the normal signaling of Purkinje cells. Changes in the chemical signals between neurons cause the episodes of uncoordinated movement seen in people with episodic ataxia.

Familial hemiplegic migraine

Several variants in the CACNA1A gene have been identified in people with familial hemiplegic migraine type 1 (FHM1). This condition is characterized by migraines with a pattern of neurological symptoms known as aura. In FHM1, the aura includes temporary numbness or weakness on one side of the body (hemiparesis). Like EA2 (described above), FHM1 is commonly associated with ataxia and nystagmus. Most of the variants that cause FHM1 change single protein building blocks (amino acids) in the CaV2.1 channel. The most common variant, known as Thr666Met or T666M, replaces the amino acid threonine with the amino acid methionine at a specific location in the CaV2.1 channel. This variant has been found in more than a dozen families.

The CACNA1A variants that cause familial hemiplegic migraine are called gain-of-function variants, because they increase the activity of Cav2.1 channels. The variants change the structure of the CaV2.1 channels. The altered channels open more easily than usual, which increases the inward flow of calcium ions. A greater influx of calcium ions through CaV2.1 channels increases the cell's release of neurotransmitters. The resulting changes in signaling between neurons lead to the development of severe headaches in people with familial hemiplegic migraine.

In some children with FHM1 or sporadic hemiplegic migraine (described below), minor head trauma can cause life-threatening brain swelling (cerebral edema) and coma. One of the CACNA1A gene variants, known as S218L, replaces the amino acid serine with the amino acid leucine at a specific location within the CaV2.1 channel. Channels with this altered subunit open even more easily than channels altered by other CACNA1A gene variants and take longer to close. Researchers suspect that the prolonged channel activity may lead to cellular changes that cause swelling and coma.

Spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is another disorder caused by CACNA1A gene variants. The major features of this condition include progressive ataxia, nystagmus, and impaired speech (dysarthria), most often beginning in a person's forties or fifties. SCA6 results from an increased number of copies (expansion) of the CAG trinucleotide repeat in the CACNA1A gene. In people with this condition, the number of CAG repeats ranges from 20 to more than 30.

An increase in the length of the CAG segment impairs the function of the α1ACT transcription factor. As a result, genes that direct the development of Purkinje cells in the cerebellum are not turned on when they should be, and the cells cannot survive. Over time, the loss of cells in the cerebellum leads to the movement problems characteristic of SCA6.

Sporadic hemiplegic migraine

Several variants in the CACNA1A gene have been found in individuals with sporadic hemiplegic migraine. The signs and symptoms of this condition are identical to those of FHM1 (described above); however, sporadic hemiplegic migraine occurs in people with no family history of the condition. As in FHM1, sporadic hemiplegic migraine caused by CACNA1A gene variants is commonly associated with migraines with auras, ataxia, and nystagmus.

CACNA1A gene variants that cause sporadic hemiplegic migraine are acquired during a person's lifetime and are not inherited. The variants change single amino acids in the CaV2.1 channel. Many of these variants are also found in families with FHM1. The altered channels are more active than usual, which increases the release of neurotransmitters. The abnormal signaling between neurons caused by these changes leads to the headaches and auras characteristic of sporadic hemiplegic migraine.

19p13.13 deletion syndrome

The CACNA1A gene is located in a region of chromosome 19 that is missing in most people with 19p13.13 deletion syndrome. As a result of this deletion, many affected individuals are missing one copy of CACNA1A and several other genes in each cell. Features associated with 19p13.13 deletion syndrome include an unusually large head size (macrocephaly), tall stature, intellectual disability, seizures, ataxia, and other health problems. Researchers are working to determine which missing genes contribute to the specific features of the disorder. Studies suggest that the loss of one copy of the CACNA1A gene may cause the seizures and ataxia seen in affected individuals. The deletion reduces the number of CaV2.1 channels produced within cells, although it is unclear exactly how a shortage of these channels is related to seizures and ataxia in people with 19p13.13 deletion syndrome.

Other disorders

Variants in the CACNA1A gene can also cause a form of developmental and epileptic encephalopathy, which is a group of conditions characterized by repeated seizures (epilepsy) and developmental delays. People with developmental and epileptic encephalopathy caused by CACNA1A gene variants often experience intellectual disability, ataxia, nystagmus, and weak muscle tone (hypotonia).

Studies suggest that some variants involved in the condition increase the activity of the CaV2.1 channels, while others reduce the activity. Researchers are working to understand how both types of changes can lead to developmental and epileptic encephalopathy.

Other Names for This Gene

• APCA
• brain calcium channel 1
• CAC1A_HUMAN
• CACNL1A4
• calcium channel, alpha 1A subunit
• calcium channel, L type, alpha-1 polypeptide, isoform 4
• calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
• CAV2.1
• HPCA
• SCA6
• Voltage-gated calcium channel subunit alpha Cav2.1

Genomic Location

Normal Function

The CACNB4 gene belongs to a family of genes that provide instructions for making calcium channels. These channels, which transport positively charged calcium atoms (calcium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals. Calcium ions are involved in many different cellular functions, including cell-to-cell communication, the tensing of muscle fibers (muscle contraction), and the regulation of certain genes.

Calcium channels are each made up of a large alpha-1 (α1) subunit, which forms the hole (pore) through which calcium ions can flow. Each channel also includes several smaller subunits, which regulate the channel's activity and interact with various proteins inside and outside the cell. The CACNB4 gene provides instructions for making a regulatory subunit called beta-4 (β4). This subunit is most often associated with calcium channels in the brain, particularly the part of the brain that is involved in coordinating movements (the cerebellum).

In the brain, calcium channels play an essential role in communication between nerve cells (neurons). These channels help control the release of neurotransmitters, which are chemicals that relay signals from one neuron to another. Researchers believe that calcium channels are also involved in the survival of neurons and the ability of these cells to change and adapt over time (plasticity).

Health Conditions Related to Genetic Changes

Episodic ataxia

Researchers have identified at least one mutation in the CACNB4 gene that is likely to cause episodic ataxia. This mutation, which was found in a French-Canadian family with episodic ataxia type 5 (EA5), changes a single protein building block (amino acid) in the calcium channel β4 subunit. Specifically, it replaces the amino acid cysteine with the amino acid phenylalanine at position 104 (written as Cys104Phe or C104F). Scientists speculate that this genetic change may alter the ability of the β4 subunit to interact with other proteins and in some way disrupt the normal function of calcium channels in the brain. It is unclear how these effects may lead to episodes of uncoordinated movement and the other signs and symptoms of episodic ataxia.

Juvenile myoclonic epilepsy

Other disorders

Mutations in the CACNB4 gene have been associated with epilepsy in a small number of families. One of these mutations prematurely stops protein production at position 482 (written as Arg482Ter or R482X). This mutation results in an abnormally shortened β4 subunit that is missing a region critical for interaction with the larger α1 subunit. Calcium channels made with the altered β4 subunit close more quickly than usual, reducing the flow of calcium ions into the cell. Impaired calcium ion transport likely disrupts communication between nerve cells, causing seizures in people with this genetic change.

Another CACNB4 mutation, Cys104Phe, appears to cause epilepsy in at least one family. This genetic change (described above) has also been found in an unrelated family with episodic ataxia. Researchers are uncertain why this single mutation appears to underlie two different neurological conditions. They suspect that other genetic and environmental factors may be involved.

Chromosomal Location

Cytogenetic Location: 2q23.3, which is the long (q) arm of chromosome 2 at position 23.3

Molecular Location: base pairs 151,832,771 to 152,099,167 on chromosome 2 (Homo sapiens Updated Annotation Release 109.20200522, GRCh38.p13) (NCBI)

Normal Function

The KCNA1 gene belongs to a large family of genes that provide instructions for making potassium channels. These channels, which transport positively charged potassium atoms (potassium ions) into and out of cells, play a key role in a cell's ability to generate and transmit electrical signals.

The KCNA1 gene provides instructions for making one part (the alpha subunit) of a potassium channel called Kv1.1. These channels are found in the brain, where they transport potassium ions into nerve cells (neurons). The flow of certain ions, including potassium, into and out of neurons regulates communication between these cells.

Health Conditions Related to Genetic Changes

Episodic ataxia

Many variants (also called mutations) in the KCNA1 gene have been identified in people with episodic ataxia type 1 (EA1). People with this form of the condition have brief episodes of poor coordination and balance (ataxia). Between episodes, many affected individuals experience myokymia, a muscle abnormality that can cause involuntary muscle cramping, stiffness, and continuous, fine muscle twitching that appears as rippling under the skin.

Most of the KCNA1 variants that cause episodic ataxia change single protein building blocks (amino acids) in the alpha subunit of the Kv1.1 channel. Some of these changes prevent the assembly of functional channels, while other variants alter the channel's structure. When Kv1.1 channels are missing or abnormal, the flow of potassium ions into neurons is reduced. This decrease in potassium ions overexcites certain neurons in the brain, which disrupts normal communication between these cells. Although changes in the brain's signals cause the episodes of uncoordinated movement seen in people with episodic ataxia, it is unclear how altered potassium ion transport causes the specific features of the condition.

Other disorders

Variants in the KCNA1 gene have been found to cause a range of signs and symptoms that affect the nervous system. In at least one family, isolated myokymia (continuous muscle twitching and spasms without episodes of ataxia) has been attributed to KCNA1 variants. Changes in this gene have also been identified in a small number of people with repeated seizures (epilepsy). Like the KCNA1 variants that cause episodic ataxia (described above), the variants that cause isolated myokymia and epilepsy reduce the flow of potassium ions through Kv1.1 channels, disrupting normal communication between neurons in the brain. Researchers are working to determine why variants in this single gene can cause several different disorders of the nervous system.

Other Names for This Gene

• AEMK
• EA1
• HBK1
• HUK1
• KCNA1_HUMAN
• KV1.1
• MBK1
• MGC126782
• MGC138385
• MK1
• potassium channel, voltage gated shaker related subfamily A, member 1
• potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia)
• RBK1
• voltage-gated potassium channel subunit Kv1.1

Genomic Location

Normal Function

The SLC1A3 gene provides instructions for making a protein called excitatory amino acid transporter 1 (EAAT1). The EAAT1 protein is primarily found in nervous system cells called glia (or glial cells), which protect and maintain nerve cells (neurons). While the protein is found in cells throughout the brain, it is most abundant in the part of the brain that is connected to the spinal cord (the brainstem) and the region of the brain involved in coordinating movements (the cerebellum).

The EAAT1 protein transports a molecule called glutamate in the brain. Glutamate is one of several brain chemicals called neurotransmitters, which allow neurons to communicate with one another. EAAT1 also transports negatively charged chlorine atoms (chloride ions).

Neurotransmitters (such as glutamate) are released from neurons and relay signals to other cells by attaching to receptor proteins on neighboring neurons. After the neurotransmitters have had their effect, they detach from their receptors and must be cleared from the spaces between neurons. Researchers have determined that EAAT1 is one of several glutamate transporters that clear excess glutamate from these spaces. This process is carefully regulated to ensure that signals are transmitted accurately throughout the nervous system. The timely removal of glutamate is also necessary to prevent a buildup of this neurotransmitter between cells, which would be toxic to neurons.

The EAAT1 protein also transports chloride ions in and out of cells. This function of the protein may help regulate the size (volume) of glia by playing a role in their intake and release of water. EAAT1 may also help maintain a normal balance of charged molecules (ions) in cells.

Health Conditions Related to Genetic Changes

Episodic ataxia

Several variants (also called mutations) in the SLC1A3 gene have been found to cause episodic ataxia type 6 (EA6), which is a nervous system disorder involving episodes of poor coordination and balance (ataxia).

The variants that cause episodic ataxia change single protein building blocks (amino acids) in the EAAT1 protein. Research shows that the altered EAAT1 proteins allow more chloride ions to flow in or out of cells than usual. Researchers suspect that glia with these altered channels cannot maintain the correct volume or ion balance, causing them to shrink and die.

The loss of glia is thought to impair the clearance of glutamate from between neurons in the brain. The excess glutamate may overexcite certain neurons, disrupting normal communication between these cells. The changes in signaling between neurons likely causes the episodes of uncoordinated movement seen in people with episodic ataxia.

Other Names for This Gene

• EA6
• EAA1_HUMAN
• EAAT-1
• EAAT1
• Excitatory amino acid transporter 1
• FLJ25094
• GLAST
• GLAST1
• Glial high affinity glutamate transporter
• Glutamate/aspartate transporter, high affinity, sodium-dependent
• Sodium-dependent glutamate/aspartate transporter 1
• solute carrier family 1 (glial high affinity glutamate transporter), member 3
• Solute carrier family 1 member 3

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the variant from one affected parent. Other cases result from new variants in the gene and occur in people with no history of the disorder in their family.

Episodic ataxia is uncommon, affecting less than 1 in 100,000 people. Only types 1, 2, and 6 have been identified in more than one family, and type 2 is by far the most common form of the condition.