Alternating hemiplegia of childhood is a neurological condition characterized by recurrent episodes of temporary paralysis, often affecting one side of the body (hemiplegia). During some episodes, the paralysis alternates from one side of the body to the other or affects both sides at the same time. These episodes begin in infancy or early childhood, usually before 18 months of age, and the paralysis lasts from minutes to days.

In addition to paralysis, affected individuals can have sudden attacks of uncontrollable muscle activity; these can cause involuntary limb movements (choreoathetosis), muscle tensing (dystonia), movement of the eyes (nystagmus), or shortness of breath (dyspnea). People with alternating hemiplegia of childhood may also experience sudden redness and warmth (flushing) or unusual paleness (pallor) of the skin. These attacks can occur during or separately from episodes of hemiplegia.

The episodes of hemiplegia or uncontrolled movements can be triggered by certain factors, such as stress, extreme tiredness, cold temperatures, or bathing, although the trigger is not always known. A characteristic feature of alternating hemiplegia of childhood is that all symptoms disappear while the affected person is sleeping but can reappear shortly after awakening. The number and length of the episodes initially worsen throughout childhood but then begin to decrease over time. The uncontrollable muscle movements may disappear entirely, but the episodes of hemiplegia occur throughout life.

Alternating hemiplegia of childhood also causes mild to severe cognitive problems. Almost all affected individuals have some level of developmental delay and intellectual disability. Their cognitive functioning typically declines over time.

Alternating hemiplegia of childhood is a rare condition that affects approximately 1 in 1 million people.

Alternating hemiplegia of childhood is primarily caused by mutations in the ATP1A3 gene. Very rarely, a mutation in the ATP1A2 gene is involved in the condition. These genes provide instructions for making very similar proteins. They function as different forms of one piece, the alpha subunit, of a larger protein complex called Na+/K+ ATPase; the two versions of the complex are found in different parts of the brain. Both versions play a critical role in the normal function of nerve cells (neurons). Na+/K+ ATPase transports charged atoms (ions) into and out of neurons, which is an essential part of the signaling process that controls muscle movement.

Mutations in the ATP1A3 or ATP1A2 gene reduce the activity of the Na+/K+ ATPase, impairing its ability to transport ions normally. It is unclear how a malfunctioning Na+/K+ ATPase causes the episodes of paralysis or uncontrollable movements characteristic of alternating hemiplegia of childhood.

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 ATP1A3 gene provides instructions for making one part (the alpha-3 subunit) of a protein known as Na+/K+ ATPase or the sodium pump. 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-3 subunit are primarily found in nerve cells (neurons) in the brain and are critical for their normal function. The movement of sodium and potassium ions helps regulate the electrical activity of these cells and plays an important role in the signaling process that controls muscle movement. The activity of Na+/K+ ATPase also helps regulate cell size (volume).

Additionally, Na+/K+ ATPase helps regulate a process called neurotransmitter reuptake. Neurotransmitters are chemicals that transmit signals from one neuron to another. After a neurotransmitter has had its effect, it must be removed quickly from the space between the neurons. The reuptake of neurotransmitters is carefully controlled to ensure that signals are sent and received accurately throughout the nervous system.

Health Conditions Related to Genetic Changes

Alternating hemiplegia of childhood

Mutations in the ATP1A3 gene are the primary cause of a neurological condition called alternating hemiplegia of childhood; at least 25 ATP1A3 gene mutations have been found in affected individuals. This condition is characterized by 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.

Most ATP1A3 gene mutations associated with alternating hemiplegia of childhood change single protein building blocks (amino acids) in the alpha-3 subunit of Na+/K+ ATPase. These genetic changes appear to impair the pump's ability to transport ions, although it is unclear how the mutations lead to the specific features of alternating hemiplegia of childhood.

Rapid-onset dystonia parkinsonism

At least nine mutations in the ATP1A3 gene have been identified in individuals and families with rapid-onset dystonia parkinsonism. Most of these mutations change single amino acids in the alpha-3 subunit of Na+/K+ ATPase. Changes in the protein's structure can reduce its activity or make it unstable. Studies suggest that the defective Na+/K+ ATPase is unable to transport sodium ions normally, which disrupts the electrical activity of neurons in the brain. However, it is unclear how a malfunctioning Na+/K+ ATPase causes the movement abnormalities characteristic of rapid-onset dystonia parkinsonism.

Other Names for This Gene

• AT1A3_HUMAN
• ATPase, Na+/K+ transporting, alpha 3 polypeptide
• DYT12
• MGC13276
• Na+/K+ -ATPase alpha 3 subunit
• Na+/K+ ATPase 3
• RDP
• sodium pump 3
• sodium-potassium-ATPase, alpha 3 polypeptide
• sodium/potassium-transporting ATPase alpha-3 chain

Genomic Location

Alternating hemiplegia of childhood is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of alternating hemiplegia of childhood result from new mutations in the gene and occur in people with no history of the disorder in their family. However, the condition can also run in families. For unknown reasons, the signs and symptoms are typically milder when the condition is found in multiple family members than when a single individual is affected.