Familial paroxysmal kinesigenic dyskinesia is a disorder characterized by episodes of abnormal movement that range from mild to severe. In the condition name, the word paroxysmal indicates that the abnormal movements come and go over time, kinesigenic means that episodes are triggered by movement, and dyskinesia refers to involuntary movement of the body.

People with familial paroxysmal kinesigenic dyskinesia experience episodes of irregular jerking or shaking movements that are brought on by sudden motion, such as standing up quickly or being startled. An episode may involve slow, prolonged muscle contractions (dystonia); small, fast, "dance-like" motions (chorea); writhing movements of the limbs (athetosis); or, rarely, flailing movements of the limbs (ballismus).

Familial paroxysmal kinesigenic dyskinesia may affect one or both sides of the body. The type of abnormal movement varies among affected individuals, even among members of the same family. In many people with familial paroxysmal kinesigenic dyskinesia, a pattern of symptoms called an aura immediately precedes the episode. The aura is often described as a crawling or tingling sensation in the affected body part. Individuals with this condition do not lose consciousness during an episode and do not experience any symptoms between episodes.

Individuals with familial paroxysmal kinesigenic dyskinesia usually first experience episodes during childhood or adolescence. Episodes typically last less than five minutes, and the frequency of episodes ranges from one per month to 100 per day. In most affected individuals, episodes occur less often with age.

In some people with familial paroxysmal kinesigenic dyskinesia the disorder begins in infancy with recurring seizures characteristic of those in a condition called benign familial infantile seizures. These seizures usually develop in the first year of life and stop by age 3. When benign familial infantile seizures are associated with familial paroxysmal kinesigenic dyskinesia, the condition is known as infantile convulsions and choreoathetosis (ICCA). In families with ICCA, some individuals develop only benign familial infantile seizures, some have only familial paroxysmal kinesigenic dyskinesia, and others have ICCA, which has features of both conditions.

Familial paroxysmal kinesigenic dyskinesia can be caused by variants (also known as mutations) in the PRRT2 gene. The protein produced from this gene helps control signaling between nerve cells (neurons) in the brain. PRRT2 gene variants, which reduce the amount of PRRT2 protein, lead to abnormal neuronal signaling. This altered activity in the brain is thought to underlie the movement problems associated with familial paroxysmal kinesigenic dyskinesia.

Not everyone with this condition has a variant in the PRRT2 gene. Variants in other genes involved in signaling in the brain are rare causes of familial paroxysmal kinesigenic dyskinesia. The genetic cause is unknown in other affected families. Noninherited (somatic) variants in the same and other genes can cause paroxysmal kinesigenic dyskinesia in people with no family history of the disorder. The nonfamilial form is referred to as sporadic paroxysmal kinesigenic dyskinesia.

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

This condition is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

Familial paroxysmal kinesigenic dyskinesia is estimated to occur in 1 in 150,000 individuals. For unknown reasons, this condition affects more males than females.