Sporadic hemiplegic migraine – ATP1A2 and CACNA1A genes 


Sporadic hemiplegic migraine (SHM), or non-familial hemiplegic migraine, is a rare form of migraine. Migraines usually cause severe, throbbing pain in one area of ​​the head. Some people with migraines also experience nausea, vomiting, and sensitivity to light and sound. These recurring headaches often begin in childhood or adolescence and can be triggered by certain foods, emotional stress, and minor head trauma. Each headache episode can last from a few hours to a few days.

In some types of migraine, including familial hemiplegic migraine, a group of neurological symptoms called an "aura" precedes the headache. The most common symptoms associated with aura are temporary visual changes, such as scotomas, flashing lights, zig-zag lines, double vision, weakness or temporary numbness that often affects one side of the body. Additional features of an aura can include slurred speech, confusion, and drowsiness. A general aura develops gradually over a few minutes and lasts for about an hour. Some people with sporadic hemiplegic migraine experience unusually severe migraine episodes. These episodes may include fever, prolonged weakness, seizures, and coma. Although most people with sporadic hemiplegic migraine fully recover between episodes, neurological symptoms such as memory loss and attention problems can last for weeks or months. Some affected individuals develop ataxia, which can worsen over time, and nystagmus. Also, some people with severe sporadic hemiplegic migraine develop some degree of intellectual disability.

This process may be due to mutations in the ATP1A2 gene (ATPase Na+/K+ transporting subunit alpha 2) and in the CACNA1A gene (calcium voltage-gated channel subunit alpha1 A). Many people with sporadic hemiplegic migraine do not have a mutation in the ATP1A2 or CACNA1A genes. Mutations in other unidentified genes are thought to be the cause of the development of this disease.

The ATP1A2 gene, located on the long arm of chromosome 1 (1q23.2), encodes the alpha-2 subunit of the protein Na+/K+ ATPase. This protein uses the energy of the adenosine triphosphate (ATP) molecule to transport Na+ out of cells and K+ into cells. Na-ATPases that include the alpha-2+/K+ subunit are found mainly in glial cells of the nervous system, which protect and maintain neurons. Through its action on glia, the protein plays a critical role in the normal function of neurons. Communication between neurons depends on neurotransmitters. To transmit signals, a neuron releases neurotransmitters, which bind to receptor proteins on neighboring neurons. After the neurotransmitters have had their effect, they detach from their receptors and move out of the spaces between the glia neurons. This process is carefully regulated to ensure that signals are accurately transmitted throughout the nervous system. Na+/K+ ATPase transport pumps help regulate this process by stimulating glia to remove neurotransmitters from interneuronal spaces. This protein also removes excess potassium ions from these spaces.

Most mutations in the ATP1A2 gene associated with sporadic hemiplegic migraine change individual amino acids in the protein Na+/K+ ATPase. These changes alter the function of the protein. Although the mutations that cause sporadic hemiplegic migraine are not as well studied as those in familial hemiplegic migraine, they are believed to have similar effects, altering the transport of sodium and potassium ions, as well as prolonging the presence of neurotransmitters between the cells. neurons. Abnormal signaling resulting from these changes gives rise to headaches and auras.

The CACNA1A gene, located on the short arm of chromosome 19 (19p13.13), encodes the alpha-1 subunit of the Cav2.1 calcium channel. This subunit forms the hole through which calcium ions can flow. These channels transport calcium ions across cell membranes, playing a key role in a cell´s ability to generate and transmit electrical signals. Calcium ions are involved in different cellular functions, including cell-to-cell communication, muscle contraction, and the regulation of certain genes. Cav2.1 channels are also thought to be involved in the survival of neurons and in the ability of these cells to change and adapt over time.

At least nine mutations in the CACNA1A gene causing sporadic hemiplegic migraine have been identified. The mutations change the structure of the Cav2.1 channel. The altered channels open more easily than usual, increasing the influx of calcium ions. An increased influx of calcium ions through the channels increases the cells´ release of neurotransmitters.

The alteration occurs in people with no history of the disease in their family. Although most cases are due to new mutations that probably occur during early embryonic development, some affected individuals inherit the genetic change that causes the disease from an affected parent. A related condition, familial hemiplegic migraine, has signs and symptoms identical to sporadic hemiplegic migraine, but occurs in multiple members of a family.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Sporadic hemiplegic migraine, by means of the complete PCR amplification of the exons of the CACNA1A and ATP1A2 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).