Familial hemiplegic migraine – CACNA1A, ATP1A2, SCN1A and PRRT2 genes 

Familial hemiplegic migraine is a form of migraine that runs in families. Migraines typically cause severe, throbbing pain in one area of ​​the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. These 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 pattern of neurological symptoms called an "aura" precedes the headaches. The most common symptoms associated with auras are temporary visual changes, such as scotomata, 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 serious migraine episodes include fever, seizures, prolonged weakness, coma, and, rarely, death. Although most people with familial hemiplegic migraine fully recover between episodes, neurological symptoms such as memory loss and attention problems can last for weeks or months. About 20 percent of people with this condition develop ataxia, which can worsen over time, and nystagmus.

Este proceso es debido a mutaciones en el gen CACNA1A, ATP1A2, SCN1A, y PRRT2. El gen CACNA1A, situado en el brazo corto del cromosoma 19 (19p13), codifica una parte (la subunidad alfa-1) de un canal de calcio llamado Cav2.1. Esta subunidad forma el orificio a través del cual los iones de calcio pueden fluir. Estos canales, transportan iones de calcio a través de las membranas celulares, desempeñando un papel clave en la capacidad de una célula para generar y transmitir señales eléctricas. Los iones de calcio están involucrados en diferentes funciones celulares, incluyendo la comunicación de célula a célula, la contracción muscular, y la regulación de determinados genes. Se cree que los canales Cav2.1 también están implicados en la supervivencia de las neuronas y en la capacidad de estas células para cambiar y adaptarse con el tiempo.

This process is due to mutations in the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes. The CACNA1A gene, located on the short arm of chromosome 19 (19p13), encodes a part (the alpha-1 subunit) of a calcium channel called Cav2.1. 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 20 mutations in the CACNA1A gene have been identified in people with familial hemiplegic migraine type 1 (FHM1). The most common mutation replaces the amino acid threonine with the amino acid methionine at position 666 of the protein (Thr666Met or T666M). 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 ATP1A2 gene, located on the long arm of chromosome 1 (1q23.2), encodes a part (the alpha-2 subunit) of the protein Na+/K+ ATPase. This protein uses the energy of the adenosine triphosphate (ATP) molecule to transport ions in and out of cells. Specifically, the pumps move sodium ions (Na+) out of cells, and bring potassium ions (K+) into cells. Na-ATPases including the alpha-2+/K+ subunit are primarily found 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 interneuronal spaces occupied by the glia. This process is carefully regulated to ensure that signals are accurately transmitted throughout the nervous system. The Na+/K+ ATPase helps regulate this process by stimulating glia to clear neurotransmitters from the spaces between neurons. This protein also removes excess potassium ions from these spaces.

More than 30 mutations in the ATP1A2 gene have been identified in people with familial hemiplegic migraine type 2 (FHM2). Most of the mutations involved in changing individual amino acids in the Na+/K+ ATPase protein. Some mutations affect the protein´s ability to transport ions. Others prevent the production of any protein from one copy of the gene in each cell. As a result, less potassium is pumped into neurons, less sodium is pumped out of these cells, and neurotransmitters persist longer in the spaces between neurons.

The SCN1A gene, located on the long arm of chromosome 2 (2q24.3), encodes a part (the alpha subunit) of the sodium channel Nav1.1. These channels are found in the brain and muscles, where they control the flow of sodium ions into cells. In the brain, Nav1.1 channels are involved in transmitting signals from one neuron to another.

At least five mutations in the SCN1A gene have been identified in people with familial hemiplegic migraine type 3 (FHM3). Each of these mutations changes the nucleotides encoding an amino acid in the Nav1.1 channel, altering the structure of the channel. The abnormal channels remain open longer than usual, increasing the flow of sodium ions into the neurons. This increase triggers the cell to release more neurotransmitters.

The PRRT2 gene, located on the short arm of chromosome 16 (16p11.2), encodes the proline-rich transmembrane protein 2 (PRRT2). The function of this protein is unknown, although it is believed to be involved in brain signalling. Studies show that it interacts with another protein called SNAP25, which is involved in signaling between neurons in the brain, controlling the release of neurotransmitters.

At least two mutations in the PRRT2 gene have been identified in people with the disease. A gene mutation inserts an extra nucleotide into the gene (649dupC). The mutations alter the blueprint used for protein synthesis and lead to the production of an abnormally short protein that is rapidly broken down. As a result, affected individuals have a shortage of the protein. This shortage is thought to affect the function of the SNAP25 protein, leading to abnormal signaling between neurons, although the mechanism causing familial hemiplegic migraine is unknown.

There is little evidence that mutations in the CACNA1A, ATP1A2, SCN1A and PRRT2 genes play a role in common migraines, which affect millions of people each year. They are looking for additional genetic changes that may underlie rare types of migraine, such as familial hemiplegic migraine, as well as more common forms of migraine.

This condition is inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, affected individuals have an affected parent. However, some people who inherit an altered gene never develop features of familial hemiplegic migraine, known as reduced penetrance. A related condition, sporadic hemiplegic migraine, has identical signs and symptoms but occurs in individuals without a family history of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Familial hemiplegic migraine, by means of the complete PCR amplification of the exons of the CACNA1A, ATP1A2, SCN1A and PRRT2 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).