The PRRT2 gene provides instructions for the proline-rich transmembrane protein 2 (PRRT2), which is located in nerve cells within the brain. This protein helps regulate signaling between neurons, a process that relies on chemicals called neurotransmitters. Neurotransmitters are stored in vesicles inside nerve cells and are released into the synapse, the junction between neurons, to be taken up by neighboring cells.
The PRRT2 protein interacts with several other proteins involved in this neurotransmitter release process. It is thought to influence the function of various ion channels, which control the flow of charged atoms into the neuron and generate electrical signals. Additionally, PRRT2 hinders the formation of the SNARE complex, a group of proteins that assist vesicles in fusing with the cell membrane to release neurotransmitters. Changes or mutations in the PRRT2 gene can disrupt these processes, potentially leading to abnormal signaling between neurons and subsequent neurological issues. These mutations often result in a reduced amount of functional PRRT2 protein, leading to altered synaptic neurotransmitter release and dysregulated neuronal excitability.
Conditions Linked to PRRT2 Mutations
Mutations in the PRRT2 gene are associated with a range of neurological disorders, often characterized by their episodic nature. One prominent condition is Paroxysmal Kinesigenic Dyskinesia (PKD), which involves sudden, involuntary movements. PRRT2 mutations are found in the majority of individuals with PKD.
Other conditions linked to PRRT2 mutations include Benign Familial Infantile Seizures (BFIS) and Infantile Convulsions and Choreoathetosis (ICCA). BFIS is characterized by seizures that typically begin in the first year of life and often resolve by two years of age. The PRRT2 gene is also associated with familial hemiplegic migraine, a type of migraine with temporary weakness or paralysis on one side of the body.
Recognizing Symptoms of PRRT2-Related Conditions
Symptoms of PRRT2-related conditions typically appear in childhood or adolescence and can vary among individuals. For Paroxysmal Kinesigenic Dyskinesia (PKD), the hallmark symptoms are sudden, involuntary movements such as dystonia, chorea, or athetosis. These episodes are often triggered by sudden movements, like standing up quickly or being startled, and can affect one side or both sides of the body. PKD attacks usually last less than a minute, though some individuals may experience up to 100 episodes daily.
In Benign Familial Infantile Seizures (BFIS), the onset of seizures typically occurs between 4 and 7 months of age, almost always within the first year of life. These seizures are often focal-onset motor seizures, meaning they begin in a specific area of the brain and may involve impaired awareness or progress to full-body tonic-clonic seizures. Seizures in BFIS can occur in clusters, with multiple brief episodes per day, sometimes every two to three hours. Infantile Convulsions and Choreoathetosis (ICCA) presents with a combination of these infantile seizures and choreoathetosis, which are involuntary, flowing, and sometimes writhing movements.
Diagnosis and Management of PRRT2-Related Conditions
Diagnosing PRRT2-related disorders primarily involves genetic testing to identify specific mutations within the PRRT2 gene. This molecular genetic testing confirms the presence of a heterozygous pathogenic variant in the gene in individuals exhibiting suggestive symptoms. Neurologists specializing in epilepsy and movement disorders typically guide the diagnostic process and subsequent management.
Management strategies are tailored to the individual’s specific neurological manifestations and the degree of functional impairment. For conditions like Paroxysmal Kinesigenic Dyskinesia (PKD), anti-epileptic drugs are often effective in reducing the frequency and severity of attacks. Avoiding known triggers such as stress, sleep deprivation, and anxiety can also help prevent PKD episodes. Benign Familial Infantile Seizures (BFIS) generally respond well to anti-seizure medications and typically resolve by the age of two. The overall outlook for many PRRT2-related disorders is generally favorable, with many conditions being benign, self-limiting, or highly responsive to appropriate treatment.