Migraine familial hemiplegic (Familial hemiplegic migraine) - Genes CACNA1A, ATP1A2, SCN1A, and PRRT2.  

Familial hemiplegic migraine is a form of migraine that runs in families. Migraines typically cause throbbing pain intense in an 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 trauma to the head. Each episode of headaches 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 "aura" precedes the headaches. The most common symptoms associated with aura are temporary visual changes such as scotoma, flashing lights, zigzag lines, double vision, weakness or temporary numbness often affects one side of the body. Additional features of an aura may include slurred speech, confusion and sleepiness. A general aura develops gradually over a few minutes and lasts about one hour. Some episodes of severe migraine include fever, seizures, prolonged weakness, coma and, rarely, death. While most people familiar hemiplegic migraine with complete recovery between episodes, neurological symptoms such as memory loss and attention problems may last weeks or months. About 20 percent of people with this condition develop ataxia, which can worsen over time, and nystagmus.

This process is due to mutations in the CACNA1A, ATP1A2, SCN1A, and PRRT2 gene. CACNA1A, located on the short arm of chromosome 19 (19p13), encoding a portion (alpha1 subunit) of a calcium channel Cav2.1 called. This subunit forms the hole through which calcium ions can flow. These channels, transport of calcium ions across cell membranes and plays a key role in the ability of a cell to generate and transmit electrical signals. Calcium ions are involved in various cellular functions including cell-cell communication, muscle contraction, and regulation of certain genes. It is believed that Cav2.1 channels are also implicated in the survival of neurons and the ability of these cells to change and adapt over time.

They have identified mutations in at least 20 CACNA1A in people with familial hemiplegic migraine type 1 (FHM1). The most common mutation, the amino acid replaces the amino acid methionine threonine in position 666 of protein (or Thr666Met T666M). Mutations change the structure of the Cav2.1 channel. Altered channels open more easily than usual, which increases the inward flow of calcium ions. Increased influx of calcium ions through the channels increases the release of neurotransmitters cells.

The ATP1A2 gene, located on the long arm of chromosome 1 (1q23.2), encoding a portion (the alpha-2 subunit) of the Na + / K + ATPase protein. This protein uses the energy of the molecule adenosine triphosphate (ATP) to transport ions into and out of cells. Specifically, the pumps draw of sodium ions (Na +) outside the cells, and introduce potassium ion (K +) into the cells. The Na-ATPases which include alpha-2 + / K + subunit is found mostly in glia cells of the nervous system which protect neurons and maintain. Through their action on glial 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 neurotransmitters have had their effect, their receptors are separated and removed from the interneuron spaces occupied by glia. This process is regulated carefully to ensure that the signals are transmitted accurately throughout the nervous system. Na + / K + ATPase helps regulate this process by stimulating glial neurotransmitters to eliminate spaces between neurons. This protein also eliminates potassium ions in excess of these spaces.

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

SCN1A gene, located on the long arm of chromosome 2 (2q24.3), encoding a portion (the alpha subunit) Nav1.1 sodium channel. These channels are in the brain and muscles, which control the flow of sodium ions into cells. In the brain, Nav1.1 channels are involved in the transmission of signals from one neuron to another.

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

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

They have identified at least two mutations in the gene PRRT2 in people with the disease. A mutation of the gene inserts an extra nucleotide in the gene (649dupC). Mutations alter the model used for protein synthesis and lead to production of an abnormally short protein rapidly it decomposes. As a result, affected individuals have a shortage of protein. It is believed that this shortage affects the function of the protein SNAP25, which leads to abnormal signaling between neurons, although the mechanism that causes 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 seeking additional genetic changes that may underlie rare types of migraine, such as familial hemiplegic migraine, as well as the most common forms of migraine.

This condition is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to cause the alteration. In most cases, affected individuals have an affected parent. However, some people who inherit an altered gene never develop characteristics of familial hemiplegic migraine, made known as reduced penetrance. A related condition, sporadic hemiplegic migraine, have signs and symptoms identical but occurs in individuals with no history of disease in your family.  

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