Rapid-onset dystonia parkinsonism is a rare movement disorder. "Rapid-onset" refers to the abrupt appearance of signs and symptoms over a period of hours to days. Dystonia is a condition characterized by involuntary, sustained muscle contractions. Parkinsonism can include tremors, unusually slow movement (bradykinesia), rigidity, an inability to hold the body upright and balanced (postural instability), and a shuffling walk that can cause recurrent falls.

Rapid-onset dystonia parkinsonism causes movement abnormalities that can make it difficult to walk, talk, and carry out other activities of daily life. In this disorder, dystonia affects the arms and legs, causing muscle cramping and spasms. Facial muscles are often affected, resulting in problems with speech and swallowing. The movement abnormalities associated with rapid-onset dystonia parkinsonism tend to begin near the top of the body and move downward, first affecting the facial muscles, then the arms, and finally the legs.

The signs and symptoms of rapid-onset dystonia parkinsonism most commonly appear in adolescence or young adulthood. In some affected individuals, signs and symptoms can be triggered by an infection, physical stress (such as prolonged exercise), emotional stress, or alcohol consumption. The signs and symptoms tend to stabilize within about a month, but they typically do not improve much after that. In some people with this condition, the movement abnormalities abruptly worsen during a second episode several years later.

Some people with rapid-onset dystonia parkinsonism have been diagnosed with anxiety, social phobias, depression, and seizures. It is unclear whether these disorders are related to the genetic changes that cause rapid-onset dystonia parkinsonism.

Rapid-onset dystonia parkinsonism is caused by mutations in the ATP1A3 gene. This gene provides instructions for making one part of a larger protein called Na+/K+ ATPase, also known as the sodium pump. This protein is critical for the normal function of nerve cells (neurons) in the brain. It 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 gene reduce the activity of the Na+/K+ ATPase or make the protein unstable. Studies suggest that the defective protein is unable to transport 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.

In some people with rapid-onset dystonia parkinsonism, no mutation in the ATP1A3 gene has been identified. The genetic cause of the disorder is unknown in these individuals. Researchers believe that mutations in at least one other gene, which has not been identified, can cause this disorder.

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

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered ATP1A3 gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits a mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Not everyone who has an ATP1A3 mutation will ultimately develop the signs and symptoms of rapid-onset dystonia parkinsonism. It is unclear why some people with a gene mutation develop movement abnormalities and others do not.

Rapid-onset dystonia parkinsonism appears to be a rare disorder, although its prevalence is unknown. It has been diagnosed in individuals and families from the United States, Europe, and Korea.