How do PRRT2 mutations trigger episodes of paroxysmal kinesigenic dyskinesia?

The mutation disrupts normal neurotransmitter release, making neurons overly excitable. Sudden movements, sudden changes in posture, or even stress can provoke a brief attack of involuntary jerking or twisting movements that typically last seconds to minutes.

Is PRRT2 inheritance predictable, and what is the chance that a child will inherit the mutation?

PRRT2 mutations are inherited in an autosomal dominant pattern. If one parent carries a pathogenic variant, each child has a 50 % chance of inheriting it. Genetic counseling and prenatal testing can help families understand their risks.

Can lifestyle changes help reduce the frequency of PRRT2‑associated attacks?

Yes. Regular sleep, avoiding sudden movements, and minimizing stress can lower trigger frequency. For dyskinesia, a structured physical therapy program focusing on controlled, slow movements can improve motor control and reduce episode severity.===

What is the first‑line medication for treating PRRT2‑related familial hemiplegic migraine?

low dose of a sodium‑channel blocker, such as carbamazepine or oxcarbazepine, is often effective in reducing both migraine frequency and aura symptoms. If seizures are also present, a combination of a benzodiazepine for acute episodes and a long‑term antiepileptic may be used.

PRRT2 gene

The PRRT2 gene encodes a neuronal protein that regulates neurotransmitter release, and pathogenic variants are linked to several paroxysmal neurological disorders such as familial hemiplegic migraine and paroxysmal kinesigenic dyskinesia.

Overview

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 (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. The 649dupC variant that causes both familial paroxysmal kinesigenic dyskinesia and familial hemiplegic migraine 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

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Tests of PRRT2

Scientific Articles on PubMed

PubMed

Catalog of Genes and Diseases from OMIM

CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS; ICCA
PROLINE-RICH TRANSMEMBRANE PROTEIN 2; PRRT2
SEIZURES, BENIGN FAMILIAL INFANTILE, 2; BFIS2

Gene and Variant Databases

NCBI Gene
ClinVar

Genomic Location

The PRRT2 gene is found on chromosome 16.

References

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