Familial hemiplegic migraine is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. These recurrent headaches typically begin in childhood or adolescence and can be triggered by certain foods, emotional stress, and minor head trauma. Each headache may 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 headache. The most common symptoms associated with an aura are temporary visual changes such as blind spots (scotomas), flashing lights, zig-zagging lines, and double vision. In people with familial hemiplegic migraine, auras are also characterized by temporary numbness or weakness, often affecting one side of the body (hemiparesis). Additional features of an aura can include difficulty with speech, confusion, and drowsiness. An aura typically develops gradually over a few minutes and lasts about an hour.

Unusually severe migraine episodes have been reported in some people with familial hemiplegic migraine. These episodes have included fever, seizures, prolonged weakness, coma, and, rarely, death. Although most people with familial hemiplegic migraine recover completely between episodes, neurological symptoms such as memory loss and problems with attention can last for weeks or months. About 20 percent of people with this condition develop mild but permanent difficulty coordinating movements (ataxia), which may worsen with time, and rapid, involuntary eye movements called nystagmus.

Sporadic hemiplegic migraine is a rare form of migraine headache. Migraines typically cause intense, throbbing pain in one area of the head. Some people with migraines also experience nausea, vomiting, and sensitivity to light and sound. These recurrent headaches typically begin in childhood or adolescence and can be triggered by certain foods, emotional stress, and minor head trauma. Each headache may last from a few hours to a few days.

In sporadic hemiplegic migraine and some other types of migraine, a pattern of neurological symptoms called an aura occurs before onset of the headache. An aura commonly includes temporary visual changes such as blind spots (scotomas), flashing lights, zig-zagging lines, and double vision. In people with sporadic hemiplegic migraine, auras are also characterized by temporary numbness or weakness, often affecting one side of the body (hemiparesis). Additional features of an aura can include difficulty with speech, confusion, and drowsiness. An aura typically develops gradually over a few minutes and lasts about an hour.

Some people with sporadic hemiplegic migraine experience unusually severe migraine episodes. These episodes can include fever, prolonged weakness, seizures, and coma. Although most people with sporadic hemiplegic migraine recover completely between episodes, neurological symptoms such as memory loss and problems with attention can last for weeks or months. Some affected individuals develop mild but permanent difficulty coordinating movements (ataxia), which may worsen with time, and rapid, involuntary eye movements called nystagmus. Mild to severe intellectual disability has been reported in some people with sporadic hemiplegic migraine.

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 ATP1A2 gene provides instructions for making one part (the alpha-2 subunit) of a protein known as a Na+/K+ ATPase. This protein uses energy from a molecule called adenosine triphosphate (ATP) to transport charged atoms (ions) into and out of cells. Specifically, it pumps sodium ions (Na+) out of cells and potassium ions (K+) into cells.

Na+/K+ ATPases that include the alpha-2 subunit are primarily found in nervous system cells called glia, which protect and maintain nerve cells (neurons). Through its action in glia, the protein plays a critical role in the normal function of neurons. Communication between neurons depends on chemicals called neurotransmitters. To relay signals, a neuron releases neurotransmitters, which attach to receptor proteins on neighboring neurons. After the neurotransmitters have had their effect, they detach from their receptors and are removed from the spaces between neurons by glia. This process is carefully regulated to ensure that signals are transmitted accurately 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.

Health Conditions Related to Genetic Changes

Alternating hemiplegia of childhood

At least one mutation in the ATP1A2 gene can cause alternating hemiplegia of childhood. The primary feature of this condition is recurrent episodes of temporary paralysis, often affecting one side of the body (hemiplegia). During some episodes, the paralysis alternates from one side to the other or affects both sides of the body at the same time. The known ATP1A2 gene mutation associated with this condition replaces a single protein building block (amino acid) in Na+/K+ ATPase: the amino acid threonine is replaced with the amino acid asparagine at protein position 378 (written as Thr378Asn or T378N). This genetic change probably impairs the protein's ability to transport ions, although it is unclear how the mutation leads to the specific features of alternating hemiplegia of childhood.

Familial hemiplegic migraine

More than 30 mutations in the ATP1A2 gene have been identified in people with familial hemiplegic migraine type 2 (FHM2). This condition is characterized by migraine headaches with a pattern of neurological symptoms known as aura. In FHM2, the aura includes temporary numbness or weakness on one side of the body (hemiparesis). Most of the mutations involved in FHM2 change single amino acids in the Na+/K+ ATPase protein. Some mutations impair the protein's ability to transport ions. Others prevent the production of any protein from one copy of the ATP1A2 gene in each cell. As a result, less potassium is pumped into neurons, less sodium is pumped out of these cells, and neurotransmitters spend more time in the spaces between neurons. The resulting changes in signaling in the brain lead people with FHM2 to develop these severe headaches.

Sporadic hemiplegic migraine

ATP1A2 gene mutations can also cause sporadic hemiplegic migraine. The signs and symptoms of this condition are identical to those of FHM2 (described above); however, sporadic hemiplegic migraine occurs in people with no family history of the condition. As in FHM2, most of the mutations associated with sporadic hemiplegic migraine change single amino acids in the Na+/K+ ATPase protein. These changes impair the function of the protein. Although the mutations that cause sporadic hemiplegic migraine are not as well-studied as those in familial hemiplegic migraine, it is thought that they have similar effects: impairing the transport of sodium and potassium ions and prolonging the presence of neurotransmitters between neurons. The abnormal signaling resulting from these changes leads to the headaches and auras characteristic of the condition.

Other Names for This Gene

• AT1A2_HUMAN
• ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide
• ATPase, Na+/K+ transporting, alpha 2 polypeptide
• FHM2
• MHP2
• Na+/K+ -ATPase alpha 2 subunit proprotein
• Na+/K+ ATPase 2
• Na+/K+ ATPase, alpha-A(+) catalytic polypeptide
• Na+/K+ ATPase, alpha-B polypeptide
• sodium pump 2
• sodium pump subunit alpha-2
• sodium-potassium ATPase
• sodium/potassium-transporting ATPase alpha-2 chain

Genomic Location

Normal Function

The SCN1A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The SCN1A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.1. These channels are primarily found in the brain, where they control the flow of sodium ions into cells. NaV1.1 channels are involved in transmitting signals from one nerve cell (neuron) to another. Communication between neurons depends on chemicals called neurotransmitters, which are released from one neuron and taken up by neighboring neurons. The flow of sodium ions through NaV1.1 channels helps determine when neurotransmitters will be released.

Health Conditions Related to Genetic Changes

Familial hemiplegic migraine

At least seven mutations in the SCN1A gene have been identified in people with familial hemiplegic migraine type 3 (FHM3), a form of migraine headache that runs in families. Each of these mutations changes a single protein building block (amino acid) in the NaV1.1 channel, which alters the channel's structure. The abnormal channels stay open longer than usual, which increases the flow of sodium ions into neurons. This increase triggers the cell to release more neurotransmitters. The resulting changes in signaling between neurons make people with FHM3 more susceptible to developing these severe headaches.

Genetic epilepsy with febrile seizures plus

Hundreds of mutations in the SCN1A gene have been found to cause genetic epilepsy with febrile seizures plus (GEFS+), which is a spectrum of seizure disorders of varying severity. These conditions include simple febrile (fever-associated) seizures, which start in infancy and usually stop by age 5, and febrile seizures plus (FS+). FS+ involves febrile and other types of seizures, including those not related to fevers (afebrile seizures), that continue beyond childhood. The GEFS+ spectrum also includes other conditions, such as Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI), that cause more serious seizures that last longer and may be difficult to control. These recurrent seizures (epilepsy) can worsen over time and are often accompanied by a decline in brain function.

The SCN1A gene mutations that underlie GEFS+ have a variety of effects on the function of the NaV1.1 channel. Some mutations change single amino acids in the channel, which alter the channel's structure. Others lead to the production of a nonfunctional version of the NaV1.1 channel or reduce the number of these channels produced in each cell. Still other mutations change single amino acids in critical regions of the channel. All of these genetic changes affect the ability of NaV1.1 channels to transport sodium ions into neurons. Some mutations are thought to reduce channel activity while others may increase it. It is unclear, however, how these genetic changes underlie the development of seizures or why they lead to a range of seizure disorders with varying severity.

Lennox-Gastaut syndrome

MedlinePlus Genetics provides information about Lennox-Gastaut syndrome

Malignant migrating partial seizures of infancy

MedlinePlus Genetics provides information about Malignant migrating partial seizures of infancy

Other disorders

A common change (polymorphism) in the SCN1A gene has been associated with the effectiveness of certain anti-seizure medications. This polymorphism, which is written as ICS5N+5G>A, alters a single DNA building block (nucleotide) in the SCN1A gene. Studies suggest that this polymorphism is associated with the maximum safe amount (dose) of the anti-seizure drugs phenytoin and carbamazepine. These drugs treat epilepsy by blocking sodium channels (such as NaV1.1) in neurons. A dose that is too small may not control seizures effectively, while a dose that is too large may cause unwanted side effects. Researchers are hopeful that doctors will be able to test for the ICS5N+5G>A polymorphism to help determine the safest and most effective dose of anti-seizure medications for each individual.

Other Names for This Gene

• GEFSP2
• HBSCI
• NAC1
• Nav1.1
• SCN1
• SCN1A_HUMAN
• sodium channel protein, brain I alpha subunit
• sodium channel, voltage gated, type I alpha subunit
• sodium channel, voltage-gated, type I, alpha
• sodium channel, voltage-gated, type I, alpha polypeptide
• sodium channel, voltage-gated, type I, alpha subunit

Genomic Location

Normal Function

The PRRT2 gene provides instructions for making the proline-rich transmembrane protein 2 (PRRT2). This protein is found in nerve cells (neurons) in the brain, and it helps regulate signaling from neuron to neuron. Communication between neurons depends on chemicals called neurotransmitters. Neurotransmitters are contained in compartments (vesicles) inside the nerve cell and are released from one neuron and taken up by neighboring neurons. The release of neurotransmitters is controlled by many processes. The flow of charged atoms (ions) into the neuron through ion channels generates and transmits electrical signals that stimulate and coordinate neurotransmitter release. In addition, the vesicles carrying neurotransmitters join (fuse) with the cell membrane to release the chemicals into the junction between neurons (the synapse).

The PRRT2 protein interacts with several proteins inside neurons that take part in the process of neurotransmitter release. PRRT2 is thought to affect the function of several types of ion channels. In addition, the PRRT2 protein impedes the formation of a group of proteins called the SNARE complex that helps vesicles fuse with the cell membrane. Through these roles, the PRRT2 protein helps regulate signaling in the brain.

Health Conditions Related to Genetic Changes

Familial hemiplegic migraine

Variants (also known as mutations) in the PRRT2 gene have been identified in people with familial hemiplegic migraine. This condition is characterized by migraine headaches with a pattern of neurological symptoms known as aura. In familial hemiplegic migraine, the aura includes temporary numbness or weakness on one side of the body (hemiparesis).

One PRRT2 gene variant that is found in multiple people with familial hemiplegic migraine inserts an extra DNA building block (nucleotide) in the gene. (This change is written as 649dupC.) This change alters the blueprint used for making the protein and leads to production of an abnormally short PRRT2 protein that is quickly broken down. As a result, affected individuals have a shortage of PRRT2 protein. Other variants likely reduce the amount or impair the function of the PRRT2 protein. Researchers speculate that a shortage of functioning PRRT2 affects the activity of ion channels and the SNARE complex, leading to abnormal signaling between neurons. It is thought that the changes in signaling in the brain lead to development of the severe headaches characteristic of the disorder.

Familial paroxysmal kinesigenic dyskinesia

Variants in the PRRT2 gene have been found to cause another neurological disorder called familial paroxysmal kinesigenic dyskinesia. This condition is characterized by episodes of involuntary jerking or shaking of the body that are triggered by sudden motion, such as standing up quickly or being startled. The 649dupC variant (described above) is the most common genetic change in familial paroxysmal kinesigenic dyskinesia. Most PRRT2 gene variants involved in this condition, including 649dupC, lead to an abnormally short protein that is quickly broken down. As a result, affected individuals have less PRRT2 protein than normal. Researchers speculate that a shortage of PRRT2 dysregulates neurotransmitter release by altering ion channel activity and SNARE complex formation. This abnormal neuronal activity is thought to underlie the movement problems characteristic of familial paroxysmal kinesigenic dyskinesia.

Other disorders

PRRT2 gene variants have been found to cause other neurological conditions, including benign familial infantile seizures (BFIS) and infantile convulsions and choreoathetosis (ICCA). BFIS is characterized by recurrent seizures that begin in infancy and usually disappear by age 2. ICCA is characterized by both benign infantile seizures like those that occur in BFIS and episodes of involuntary movements like those that occur in familial paroxysmal kinesigenic dyskinesia (described above). The 649dupC variant that causes both familial paroxysmal kinesigenic dyskinesia and familial hemiplegic migraine (described above) can also cause BFIS and ICCA. It is unclear how this variant can cause one condition in some people and a different condition in others.

Although they have been described as separate disorders, researchers speculate that paroxysmal kinesigenic dyskinesia, BFIS, ICCA, and familial hemiplegic migraine may represent a spectrum of related disorders. In some families with a PRRT2 gene variant, affected individuals have different conditions; for example, one may have paroxysmal kinesigenic dyskinesia and another may have familial hemiplegic migraine. Rarely, PRRT2 gene variants are associated with paroxysmal dyskinesia during sleep (called paroxysmal hypnogenic dyskinesia) or recurrent episodes of poor coordination and balance (which is known as episodic ataxia). Sometimes, an affected individual has the features of more than one of these related conditions. In addition, the same genetic change can be involved in all of these conditions. A combination of environmental and genetic factors may influence the pattern of signs and symptoms an affected individual develops.

Other Names for This Gene

• dispanin subfamily B member 3
• DKFZp547J199
• DSPB3
• EKD1
• FLJ25513
• IFITMD1
• interferon induced transmembrane protein domain containing 1
• PKC
• proline-rich transmembrane protein 2
• PRRT2_HUMAN

Genomic Location

The symptoms and severity can vary considerably among people with hemiplegic migraine. Signs and symptoms associated with aura may include:

• Visual disturbance (e.g. blind spots, flashing lights, zigzag pattern, and double vision)
• Sensory loss (e.g., numbness or paresthesias of the face or an extremity)
• Difficulty with speech (which usually occur along with right-sided weakness)

Motor weakness involves areas affected by sensory symptoms and varies from mild clumsiness to complete deficit. Affected people may also experience neurologic symptoms such as confusion, drowsiness, impaired consciousness, coma, psychosis, and/or memory loss. Neurologic symptoms can last for hours to days. Attention and memory loss can last weeks to months. However, permanent motor, sensory, language, or visual symptoms are extremely rare.

Hemiplegic migraine is diagnosed based on the presence of specific signs and symptoms. Genetic testing is not necessary for all affected people.

The diagnosis is based on the presence of having at least 2 attacks with:

• aura accompanied by fully reversible motor weakness and fully reversible visual, sensory, and/or speech/language symptoms; and
• at least 2 of the following 4 characteristics:
  • at least one aura symptom that spreads gradually over ≥5 minutes, and/or two or more symptoms that occur in succession
  • each individual non-motor aura symptom lasting 5 to 60 minutes, and motor symptoms lasting
  • at least one unilateral (one-sided) aura symptom
  • the aura being accompanied by headache, or followed by headache within one hour

Additionally, all other potential causes for the symptoms need to be ruled out (such as transient ischemic attack and stroke). While the criteria requires fully reversible symptoms, it is known that some people with severe attacks may have permanent neurological problems.

A diagnosis of familial hemiplegic migraine also requires that at least one first or second degree relative has had attacks that meet the above diagnostic criteria. A diagnosis of sporadic hemiplegic migraine requires that no first or second degree relative has had attacks that meet the above criteria.

Treatment of hemiplegic migraine varies depending on severity and which symptoms are most problematic for the patient. In general, treatments aim to manage symptoms. Drugs that are effective in the prevention of common migraines may be used in hemiplegic migraine. Prophylactic management is applied to patients with frequent, long lasting, or severe attacks. Examples of migraine drugs that have been tried with variable success in people with hemiplegic migraine, include oral verapamil, acetazolamide, lamotrigine.

There are a few articles describing the use of nasal administration of ketamine, intravenous verapamil, and triptans for treatment of aura in people with hemiplegic migraine. Use of triptans in hemiplegic migraine is controversial and may be contraindicated in people with severe attacks.

For further information on these and other treatments, we recommend that you speak with your healthcare provider.