The PRRT2 gene provides instructions for making the proline-rich transmembrane protein 2, a significant component of the nervous system. This protein is highly concentrated in neurons, where it regulates the chemical signals necessary for brain function. When the gene is altered, the resulting protein malfunction leads to a variety of episodic neurological conditions, including certain seizure and movement disorders.
The Role of PRRT2 in Neural Communication
The PRRT2 protein is found almost exclusively in the presynaptic terminal of neurons, the end of the nerve cell that sends signals to the next cell. Its primary job is to regulate the release of chemical messengers called neurotransmitters into the synapse, the gap between two neurons. It influences the speed and efficiency of this communication process.
The PRRT2 protein interacts with the SNARE complex, the machinery responsible for fusing neurotransmitter-filled vesicles with the cell membrane for release. This interaction is connected with the calcium-sensing mechanism that triggers neurotransmitter release. Loss of PRRT2 function impairs this synchronous release, making the neuronal network unstable and susceptible to sudden electrical events.
Improper functioning of the PRRT2 protein disrupts the balance of signaling in the central nervous system, including the brain, basal ganglia, and cerebellum. This dysregulation of communication between nerve cells is the underlying reason for the paroxysmal, or sudden and episodic, nature of the linked disorders.
Genetic Changes and Inheritance Patterns
Genetic alterations in the PRRT2 gene cause the protein to be non-functional or absent, leading to clinical symptoms. The most common change is a single-nucleotide duplication (c.649dupC), which introduces an error in the gene’s instructions. This error typically leads to a frameshift mutation, resulting in a shortened, unstable protein that is quickly degraded.
The disorders caused by PRRT2 are usually inherited in an autosomal dominant pattern. This means a person only needs to inherit one copy of the altered gene from one parent to have an increased chance of developing the condition. Each child of an affected individual has a 50% chance of inheriting the altered gene. However, not everyone who inherits the altered gene develops symptoms, a concept known as reduced penetrance.
Approximately 90% of individuals diagnosed with a PRRT2-related disorder inherited the change from a parent, who may have had different or no symptoms. The high variability in symptoms is known as variable expressivity, meaning family members with the same genetic change can present with distinct neurological issues.
Conditions Linked to PRRT2 Malfunction
Malfunction of the PRRT2 gene results in a spectrum of overlapping neurological conditions characterized by sudden, episodic attacks. The core disorders linked to PRRT2 are Paroxysmal Kinesigenic Dyskinesia (PKD), Benign Familial Infantile Seizures (BFIS), and the combination of the two, historically known as Infantile Convulsions with Choreoathetosis (ICCA).
Paroxysmal Kinesigenic Dyskinesia (PKD) is the most common PRRT2-associated disorder, characterized by brief, involuntary movement attacks. “Kinesigenic” means the attacks are triggered by sudden voluntary movement, such as standing up, starting to run, or being startled. Episodes typically involve abnormal movements like sustained muscle contractions (dystonia), rapid jerks (chorea), or flailing movements (ballismus).
PKD attacks are short, usually lasting less than one minute, and the person remains conscious throughout the episode. Onset typically occurs in childhood or adolescence, often around age 10, with attack frequency ranging from rare to 100 times a day. In contrast, Benign Familial Infantile Seizures (BFIS) are characterized by focal seizures that begin in the first year of life, typically between 3 and 12 months of age.
Seizures in BFIS usually occur in clusters and may involve symptoms like staring, head deviation, or generalized limb jerks. They generally resolve completely by age two or three. The ICCA syndrome represents the overlap, where an individual experiences infantile seizures followed later in life by the movement attacks of PKD. A key difference is that dyskinesia is a movement disorder triggered by motion and does not involve loss of consciousness, while a seizure is an electrical disturbance in the brain.
Diagnosis and Management Approaches
Diagnosis of a PRRT2-related disorder is definitively made through molecular genetic testing. Clinical suspicion is usually raised by the characteristic symptoms, especially the episodic nature and family history of similar paroxysmal events. Genetic testing can focus specifically on the PRRT2 gene or be performed as part of a larger epilepsy or movement disorder gene panel.
Management of these conditions is effective and primarily involves anti-epileptic medications. For Paroxysmal Kinesigenic Dyskinesia (PKD), low doses of anti-seizure drugs, particularly carbamazepine or oxcarbazepine, are the first-line treatment. The response rate to these medications for PKD is high, often leading to a complete cessation of attacks.
The prognosis for PRRT2-related disorders is generally favorable, especially for the infantile seizure phenotype, which resolves spontaneously in early childhood. Although some patients with BFIS may later develop PKD, intellectual and developmental outcomes are typically normal. In addition to medication, individuals with PKD are advised to identify and avoid non-kinesigenic triggers like stress, anxiety, or sleep deprivation to manage attack frequency.