Years published: 2023
NORD gratefully acknowledges Madeline Cesarone, Genetic Counseling Student, Baylor College of Medicine, Kate Richardson, MS, CGC and Hope Northrup, MD, McGovern Medical School, UTHealth Houston, for the preparation of this report.
PRRT2-associated paroxysmal movement disorders are a group of rare movement and seizure disorders caused by changes (disease-causing variants or mutations) in the PRRT2 gene. They include a spectrum of specific disorders including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and hemiplegic migraine (HM). It’s important to note that these disorders can also have different genetic causes.
PRRT2-associated paroxysmal movement disorders are reported to have variable expressivity and reduced penetrance. Variable expressivity means that there is a range of symptoms that can occur in people affected with this genetic condition. Reduced penetrance is when not all people with a disease-causing genetic change will have symptoms. The average age of onset for PRRT2– paroxysmal kinesigenic dyskinesia is in childhood or adolescence. It is characterized by sudden attacks of involuntary movement that can be either unilateral (one side of the body) and bilateral (both sides of the body). The term kinesigenic means that the movement episodes are triggered by sudden movement or intention to move, while the term paroxysmal means that the abnormal movements come and go over time. Many PKD episodes last less than one minute but patients can have multiple in a day, some as high as 100. BFIE is defined by complex partial seizures or localization-related epilepsy with the onset being in the first year of life with resolution by 2 years old. Patients can experience multiple seizures per day occurring every 2-3 hours on average. PKD/IC is a combination of PKD and BFIE meaning that a patient would experience both seizures and PKD episodes of involuntary movement. Hemiplegic migraines are a specific type of migraine with aura, where the migraines are associated with temporary (transient) motor weakness or temporary paralysis of half of body (hemiparesis).
PRRT2-associated paroxysmal movement disorders include a wide and evolving spectrum of paroxysmal diseases.
The PRRT2 gene encodes a protein that is involved in releasing neurotransmitters. Neurotransmitters are chemicals that carry messages (chemical signals) from one nerve cell to the target cell (which can be another nerve cell or muscle cell). Healthy neurotransmitters are constantly going between cells to carry messages and instructions. Improper functioning of neurotransmitters can cause dysregulation of the signals in a person’s central nervous system (brain and spinal cord). When nerve cells are not getting the proper signals, it can lead to the medical problems associated with PRRT2-associated paroxysmal movement disorders.
paroxysmal kinesigenic dyskinesia (PKD)
The primary movement disorder associated with PRRT2 is paroxysmal kinesigenic dyskinesia (PKD). This is the most common type of paroxysmal dyskinesia. PKD attacks often occur in childhood and are thought to be induced by sudden movements, which can include being startled, going from walking to running, stress, or rapid, deep breathing (hyperventilation). Around 10% of people report having a warning sign of numbness or paresthesia in the limbs or face prior to the attack. It is often described as a crawling sensation in the affected areas. The attacks are characterized by abnormal muscle contraction (dystonia) and episodes of unwanted, uncontrollable movements, often of the muscles in the arms, legs, face and body (choreoathetosis). Additionally, patients can sometimes have irregular, frequently violent movements of the shoulder and arm while awake (ballism). Most attacks are brief, lasting only a few seconds to a minute, but some have been reported to last for as long as five minutes. There is significant variability in the frequency of attacks ranging from one per week to 100 per day. The average age of onset for PKD is 10 years old but can range from 1-20 years old, with attacks becoming less frequent with age. Common triggers for episodes are stress, sleep deprivation, fevers, and anxiety. Avoiding these in conjunction with specific medications can help reduce the number of episodes a patient experiences.
Hemiplegic migraines are a rare type of migraine headache with sensory symptoms called aura that can include flashes of light, blind spots, or tingling. This can cause temporary paralysis on one side of the body. They are often accompanied by other neurological symptoms such as visual disturbances, confusion and difficulty speaking. Common triggers for hemiplegic migraines are stress, anxiety, heat or light. The age of onset for hemiplegic migraines can be as early as late childhood but are more commonly seen during puberty or early adulthood. It also has a range of frequency with some reporting as many as a few per week to only one per month. The duration of the migraine attacks also varies greatly from only fifteen minutes to three days. Individuals report that the frequency of migraines decreases over time with many claiming complete remission during adulthood. It has also been documented that there is improvement of hemiplegic migraines during pregnancy.
benign infantile epilepsy
Benign familial infantile seizures (BFIS) are a rare form of epilepsy that typically begin during the first twelve months of life in otherwise healthy children. This condition is characterized by sudden jerking movements, eye deviation, or staring spells and are often triggered by excitement or fever. These seizures are characterized as self-limiting, meaning they stop on their own without intervention and are not known to cause any long-term neurological damage. Because of this, treatment is not typically required. Many times, the seizures diminish greatly or completely resolve by early childhood.
Less Common Signs and Symptoms
Episodic ataxia is a neurological disorder characterized by recurrent episodes of unsteadiness and lack of coordination that vary in duration. Additional symptoms that can be seen are progressive, weakness between episodes (inter-attack weakness), dystonia and unbalanced walking (ataxia). Often these symptoms are due to differences in the cerebellum, the part of the brain that controls balance for walking and standing. Triggers that have been well documented for episodes of ataxia include stress, caffeine, hormonal changes and fatigue. The mechanism that causes the episodes is unknown. It has been noted that symptoms sometimes go away on their own or the severity lessens.
Paroxysmal torticollis is a rare condition in which there are recurrent episodes of head tilting associated with irritability, vomiting, hypotonia, malaise (discomfort) and/or pallor (pale appearance). Onset begins in infancy and typically resolves between two to five years of age with the frequency being two to three times a month, but lessens as the child ages. The episodes typically last around ten minutes, but they have been reported to last as long as two months. It has been proposed that an episode is a precursor for migraines in older children. There is currently no specific treatment for this condition. Many families have used over-the-counter pain and nausea medication to aid in treating with varying degrees of success.
familial paroxysmal non-kinesigenic dyskinesia
Familial paroxysmal non-kinesigenic dyskinesia is a condition where there are unilateral or bilateral involuntary movements. Typically, episodes are triggered by alcohol, tea, coffee, excitement, stress, fatigue, or can be spontaneous. The onset of these episodes is typically in early childhood or early teens but can be as late as 50 years old. They can range from minutes to hours, but rarely occur more than once a day.
PRRT2-associated paroxysmal movement disorders are caused by changes (pathogenic variants or mutations) in the PRRT2 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working in the body. Depending on the function of the protein, it can affect many parts of the body.
The PRRT2 gene provides instructions for a protein involved in the release of neurotransmitters (chemical messengers) in the brain. The neurotransmitters are needed for proper communication from the brain to the rest of the body. Genetic changes in PRRT2 lead to abnormally short PRRT2 protein that causes an imbalance in neurotransmitter levels and causes the communication in the brain to not work properly leading to medical problems.
The PRRT2 gene holds instructions for creating (encoding) the protein named proline-rich transmembrane protein 2. It is involved in synaptic transmission. Currently, there are more than 90 pathogenic variants reported with c.649dup (p.R217Pfs*8) being the pathogenic variant present in 80% of affected individuals. Most of the known pathogenic variants are nonsense or frameshift variants that lead to truncation of the protein (creating a shorter or smaller protein).
Additionally, there have been patients identified with a 16p11.2 microdeletion. This is a deletion on the 16th chromosome that includes PRRT2 in addition to other neighboring genes. This happens in less than 1% of affected individuals. Similarly, homozygous PRRT2 pathogenic variants (people with two genetic changes, one in each of their two copies of PRRT2) occurs less than 1% of time and typically causes more severely affected individuals.
PRRT2-associated paroxysmal movement disorders follow an autosomal dominant pattern of inheritance. This means that an individual only needs a single pathogenic variant (referred to also as heterozygous) in the PRRT2 gene to cause medical problems. The non-working gene can be inherited from either parent or can be the result of a new genetic change in the individual (known as de novo). Approximately 90% of pathogenic variants are inherited from a parent. Males and females have the same level of risk, and the risk of passing a non-working gene to children is 50% for each pregnancy.
In 2015, Ebrahimi-Fakhari, et al reported that there were about 600 individuals with PRRT2-BFIE, 560 with PRRT2-PKD and 210 with PRRT2-PKD/IC. These researchers also estimated that the prevalence of PRRT2-PKD is 1:150,000 individuals. PRRT2-PKD appears to be 1.5-times more common in males than females. However, rare disorders like PRRT2-associated paroxysmal movement disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
A diagnosis of PRRT2-associated paroxysmal movement disorders is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the PRRT2 gene. A clinical diagnosis cannot be used for this disorder.
There is currently no cure for PRRT2-associated paroxysmal movement disorders but there have been studies that support specific medication for patients affected with these disorders. Treatment for patients is based on what medical problems are present in a person. Many times, treatment and management can be carried out by a neurologist in addition to a patient’s primary care provider (PCP) or pediatrician. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
PKD and infantile seizures can be treated using antiepileptic drugs (AEDs), with carbamazepine being the most effective and phenytoin, valproate, oxcarbazepine, lamotrigine, levetiracetam, or topiramate being other effective options. If the seizures last longer than five minutes or are in clusters, then individuals often respond well to a class of drugs named benzodiazepines. To reduce the frequency of seizures, it is also important to treat fevers promptly with standard over the counter medication. For PKD, avoiding known triggers such as anxiety, stress, lack of sleep, and others has been shown to be successful in limiting the frequency of attacks. It is recommended that individuals with PKD be monitored by a neurologist every 1-2 years to evaluate medication and dosing.
There is no specific treatment for hemiplegic migraines but can be managed with medications for typical migraines with aura that do not contain agents that could increase the chance of low blood flow to the heart (ischemia). Episodes are mainly treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin and naproxen as well as antiemetics to prevent nausea. There have been some reports that show success with using intranasal ketamine at the onset of an attack.
As for paroxysmal torticollis, there is currently no treatment, but families have used over-the-counter pain and nausea medication to aid in treatment with varying degrees of success. Since it is suspected to be a sign of migraines NSAIDs and antiemetics are used to help treat.
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Greene KA, Lu V, Luciano MS, et al. Benign paroxysmal torticollis: Phenotype, natural history, and quality of life. Pediatric Research. 2021;90(5):1044-1051. doi:10.1038/s41390-020-01309-1
Riant F, Roos C, Roubertie A, et al. Hemiplegic migraine associated with prrt2 variations.Neurology. 2021;98(1). doi:10.1212/wnl.0000000000012947
Zhao S, Li L, Chen Y, et al. Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2‐related disorders. CNS Neuroscience & Therapeutics. 2019;26(1):39-46. doi:10.1111/cns.13147
Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain. 2015;138(12):3476-3495.doi:10.1093/brain/awv317
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Riant F, Roze E, Barbance C, et al. PRRT2 mutations cause hemiplegic migraine. Neurology. 2012;79(21):2122-2124. doi:10.1212/wnl.0b013e3182752cb8
Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW. Primary episodic ataxias: Diagnosis, pathogenesis and treatment. Brain. 2007;130(10):2484-2493. doi:https://doi.org/10.1093/brain/awm126
Ebrahimi-Fakhari D, Moufawad El Achkar C, Klein C. PRRT2-Associated Paroxysmal Movement Disorders. 2018 Jan 11. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK475803/ Accessed June 12, 2023.
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