CACNA1A

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.

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 (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.

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.

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.

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.