Summary
Clinical characteristics.
PRRT2-related disorder, caused by heterozygous pathogenic variants in the gene PRRT2 (associated with aberrant synaptic transmission), is characterized by three core episodic neurologic phenotypes: epilepsy, movement disorder, and migraine. Age at onset and phenotypes range from neonatal/infantile (self-limited [familial] infantile epilepsy), to childhood (childhood absence epilepsy), to adolescence to adulthood (paroxysmal kinesigenic dyskinesia [PKD] or migraine). As individuals with PRRT2-related disorder age, they may exhibit one of more of these core phenotypes in various combinations, either concurrently or sequentially. Additionally, family members with the same pathogenic PRRT2 variant may display different core phenotypes.
Diagnosis/testing.
The diagnosis of PRRT2-related disorder is established in a proband with suggestive findings and a heterozygous PRRT2 pathogenic variant identified by molecular genetic testing.
Management.
Treatment of manifestations: Neurologists experienced in epilepsy and movement disorders can tailor treatment based on the primary neurologic manifestations or movement disorder phenomenology, taking into consideration degree of functional impairment, potential comorbidities, and potential medication interactions, if applicable.
Surveillance: Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires regularly scheduled follow up with the treating neurologist as well as educators and social services.
Agents/circumstances to avoid: For self-limited (familial) infantile epilepsy, treat fevers promptly. For PKD, avoid known triggers (stress, sleep deprivation, and anxiety) or other triggers to help prevent attacks and lower attack frequency. For migraine, use triptans and dihydroergotamine with caution due to the increased risk of ischemic vascular events.
Pregnancy management: Because prenatal exposure to anti-seizure medications (ASMs) may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken), discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception.
Genetic counseling.
PRRT2-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner. (Biallelic PRRT2 pathogenic variants, observed in <1% of individuals with PRRT2 pathogenic variants, are most commonly associated with a more severe phenotype.) About 90% of individuals diagnosed with PRRT2-related disorder have an affected parent or other family member. Reduced penetrance and variable expressivity are commonly observed, leading to considerable phenotypic variability among heterozygous family members. Each child of an individual with a heterozygous PRRT2 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the PRRT2 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
PRRT2-related disorder (PRRT2-RD) should be considered in individuals with any one of the following core phenotypes and/or in individuals with a paroxysmal movement disorder and a positive family history of any of the core phenotypes.
Self-Limited (Familial) Infantile Epilepsy (SeLIE)
SeLIE is characterized by the following clinical and supportive findings [Millevert et al 2023].
Paroxysmal Kinesigenic Dyskinesia (PKD)
PKD is characterized by the following clinical and supportive findings [Bruno et al 2004]:
Clinical findings. Sudden attacks of unilateral or bilateral involuntary movements (i.e., dyskinesias that can include a combination of dystonia, chorea, ballism, or athetosis) and the following:
Onset between ages 1-18 years
A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
An aura preceding attacks (10% of persons)
Short duration (typically <1 min)
High frequency (can be as many as 100 times per day)
No loss of consciousness or pain
Prevention or control w/carbamazepine
Supportive findings
Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC)
PKD/IC is characterized by symptoms fulfilling the below criteria:
Hemiplegic Migraine (HM)
HM, as defined by the International Classification of Headache Disorders, 3rd edition [Headache Classification Committee of the International Headache Society (IHS) 2018] (full text), is characterized by the following clinical and supportive findings:
Family history is consistent with autosomal dominant inheritance (e.g., males and females in multiple generations with the same or different PRRT2-related features). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of PRRT2-related disorder is established in a proband with suggestive findings and a heterozygous PRRT2 pathogenic variant (or likely pathogenic variant) identified by molecular genetic testing [Chen et al 2011, Wang et al 2011, Ebrahimi-Fakhari et al 2015] (see Table 1).
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous PRRT2 variant of uncertain significance does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).
Option 1
An epilepsy, movement disorder (i.e., dystonia or ataxia), or hemiplegic migraine multigene panel that includes PRRT2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive
genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of PRRT2 pathogenic variants reported (i.e., nonsense, missense, or deletions) are within the coding regions of the gene and are likely to be identified on exome sequencing.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in PRRT2-Related Disorder
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Identified by Method |
|---|
|
PRRT2
| Sequence analysis 3 | 99% 4 |
| Gene-targeted deletion/duplication analysis 5 | <1% 4 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Clinical Characteristics
Clinical Description
PRRT2-related disorder encompasses a spectrum of three core phenotypes: epilepsy, paroxysmal movement disorders, and migraine (see Table 2). As individuals with PRRT2-related disorder age, they may exhibit one of more of these core phenotypes in various combinations, either concurrently or sequentially. For instance, an individual initially presenting with self-limiting infantile epilepsy may later develop paroxysmal kinesigenic dyskinesia. Intrafamilial variability is also common, meaning that different combinations of the core phenotypes may appear among family members who are heterozygous for the same PRRT2 pathogenic variant.
To date, more than 1,500 individuals have been identified with a heterozygous PRRT2 pathogenic variant [Ebrahimi-Fakhari et al 2015]. The following description of the phenotypic features associated with PRRT2-related disorder is based on this report (see Table 3).
Epilepsy
Self-limited (familial) infantile epilepsy (SeLIE). Seizures are primarily focal-onset motor seizures with or without impaired awareness and focal to bilateral tonic-clonic seizures that occur independent of a fever. These seizures are brief and frequently occur in clusters, with multiple clusters per day. Ictal EEGs often report onset originating in temporal, central, parietal, or occipital areas, with or without secondary generalization [Caraballo et al 2002].
Less common seizure semiologies include motor arrest, decreased responsiveness, and automatisms [Watanabe et al 1987].
Seizures rarely progress to status epilepticus. While respiratory depression can occur either during seizures or from medications such as benzodiazepines, sudden unexpected death in epilepsy (SUDEP) and long-term sequelae have not been reported.
The interictal EEG for most individuals is unremarkable. Nevertheless, in rare instances interictal focal epileptiform discharges may be detected, including bilateral centrotemporal spikes [Seo & You 2016], bilateral parietotemporal spikes [Torisu et al 2014], and unilateral frontocentral spikes [El Achkar et al 2017].
Prognosis is favorable. Seizures generally show a complete response to first-line anti-seizure medications (ASMs). In most children seizures remit by age two years and developmental outcomes are normal.
Movement Disorders
Paroxysmal kinesigenic dyskinesia (PKD). To date, the primary paroxysmal movement disorder seen in PRRT2-related disorders is PKD. Paroxysmal attacks are often characterized by dystonia, choreoathetosis, and/or ballism. These episodes are stereotyped, i.e., typically bilateral, most commonly involving the arms, followed in decreasing order by the legs, trunk, face, and neck.
Onset of PRRT2-related PKD is in childhood or adolescence (mean age: 10.3±4.9 years; range: age 1-20 years). It appears to be about 1.5-fold more common in males than females [Ebrahimi-Fakhari et al 2015].
Dyskinesias in PRRT2-related PKD are often provoked by kinesigenic triggers such as sudden voluntary movements, intention to move, and/or accelerations in movement. However, up to 40% of individuals can experience non-kinesigenic triggers, such as anxiety, startle, sleep deprivation, and/or sustained exercise, suggesting an overlap with other subtypes of paroxysmal dyskinesias, including a small number of individuals who meet clinical criteria for paroxysmal non-kinesigenic dyskinesia [Liu et al 2012, Becker et al 2013, Liu et al 2013, Wang et al 2013, Delcourt et al 2015], paroxysmal exercise-induced dyskinesia [Liu et al 2012], paroxysmal torticollis [Dale et al 2012], paroxysmal hypnogenic dyskinesia [Liu et al 2016],and episodic ataxia [Gardiner et al 2012, Labate et al 2012, Delcourt et al 2015]. Caffeine and alcohol are also reported precipitating factors.
In about 10% of affected individuals, PKD attacks are preceded by a nonspecific aura including a crawling sensation in the affected limb, paresthesias, or nonspecific epigastric discomfort.
Attacks are usually brief – in the range of a few seconds – but can last five or more minutes in some individuals. Episodes often respond well to ASMs, most commonly carbamazepine (see Management, Treatment of Manifestations).
The frequency of attacks, which can range from 100 per day to one per week, tends to decrease with age and may resolve completely in mid- or late adulthood [Ebrahimi-Fakhari et al 2015]. Improvement during pregnancy has also been observed [Bruno et al 2004].
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC). Approximately 30% of individuals with PKD have a history of SeLIE leading to the diagnosis of PKD/IC. In some individuals seizures can also be seen in other contexts such as childhood febrile seizures or generalized seizures in adulthood. While it is unknown to date how frequently SeLIE evolves into PKD/IC, paroxysmal movement disorders in these individuals typically begin in early childhood.
Migraine
Hemiplegic migraine (HM) falls within the classification of migraines with aura subtype related to cortical spreading depression. Episodes are characterized by a transient motor manifestation, typically some degree of hemiparesis.
Migraine with or without aura. Other types of auras comprise the following (in order of frequency):
Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
Sensory loss (e.g., numbness or paresthesia)
Speech symptoms (e.g., dysarthria)
Less commonly, pathogenic PRRT2 variants are associated with migraine with or without aura.
Intrafamilial and Interfamilial Variability
Considerable variability in phenotype is seen both within and between families with the same PRRT2 pathogenic variant.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified in PRRT2-related disorder [Ebrahimi-Fakhari et al 2015].
Penetrance
The penetrance of PRRT2-related disorder ranges from 50% to 90% [van Vliet et al 2012]; thus, individuals heterozygous for a known PRRT2 pathogenic variant may be clinically unaffected.
Among the core phenotypes, penetrance is estimated to be 75%-95% for PRRT2-related SeLIE, 50%-61% for PRRT2-related PKD, and up to 87% for PRRT2-related HM [Riant et al 2022].
Nomenclature
Self-limited (familial) infantile epilepsy (SeLIE) was formerly known as benign familial infantile epilepsy (BFIE) or benign familial infantile seizures (BFIS). In the 2017 International League Against Epilepsy (ILAE) classification, the term "benign" was updated to "self-limited", emphasizing the notion that seizures typically resolved during early infancy and were associated with favorable developmental outcome [Scheffer et al 2017].
Paroxysmal kinesigenic dyskinesia (PKD) was formerly known as paroxysmal kinesigenic choreoathetosis (PKC).
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) was formerly known as infantile convulsions and choreoathetosis (ICCA).
In the International Parkinson and Movement Disorder Society Task Force Recommendations for Nomenclature of Genetic Movement Disorders, paroxysmal (Px) movement disorders (MD) associated with PRRT2 pathogenic variants are designated PRRT2-PxMD [Marras et al 2016, Lange et al 2022].
Prevalence
Prevalence for PKD, the most common of the paroxysmal movement disorders (including both PRRT2-related PKD and PKD of unknown or secondary cause), has been estimated at 1:150,000 individuals [Ebrahimi-Fakhari et al 2015].
To date, more than 600 individuals with PRRT2-related SeLIE, more than 550 individuals with PRRT2-related PKD, and more than 200 individuals with PRRT2-related PKD/IC have been reported [Ebrahimi-Fakhari et al 2015].
Management
No clinical practice guidelines for PRRT2-related disorder have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PRRT2-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Treatment of Manifestations
There is no cure for PRRT2-related disorder. Therapeutic options are tailored depending on the primary neurologic manifestations or movement disorder phenomenology (see Table 5). Decisions regarding treatment should take into consideration degree of functional impairment, potential comorbidities, and potential medication interactions, if applicable.
Self-limited (familial) infantile epilepsy (SeLIE). In most individuals, seizures respond well to conventional anti-seizure medications (ASMs) at therapeutic doses [Ebrahimi-Fakhari et al 2015]. While the efficacy of carbamazepine or oxcarbazepine specifically lacks extensive study, these tend to be the preferred ASMs given their effectiveness for the core phenotypes of PRRT2-related paroxysmal kinesigenic dyskinesia (PKD) and, anecdotally, PRRT2-related hemiplegic migraine. Clinical experience of the authors suggests that seizures in SeLIE respond to first-line ASMs, including medications that reach a therapeutic level quickly, such as phenobarbital in neonates and levetiracetam or lacosamide in infants [D Ebrahimi-Fakhari, personal observations].
Rescue medications (commonly benzodiazepines including lorazepam, diazepam, or midazolam) are crucial during seizures that last more than five minutes or seizure clusters.
Currently, no proven interventions reduce the risk of individuals with SeLIE to develop PKD later in life. Management strategies primarily focus on seizure control and monitoring developmental progress.
Paroxysmal kinesigenic dyskinesia (PKD). Management involves low-dose ASMs that reduce attack frequency and minimize secondary complications such as falls and disruptions to activities such as driving.
Sodium channel blockers including carbamazepine or oxcarbazepine remain the first-line treatment, unless contraindicated. Notably, the required doses are generally lower than those used to treat epilepsy, with reported control at doses around 100 mg/day in most individuals.
Other ASMs including levetiracetam, lacosamide, phenytoin, valproate, lamotrigine, or topiramate may also be effective and offer alternatives when first-line options are unsuitable.
Lifestyle modifications, including avoiding known triggers such as stress, sleep deprivation, or anxiety, can reduce the frequency of PKD episodes.
No other pharmacotherapies or non-pharmacologic treatments have been investigated systematically.
Hemiplegic migraine (HM). Anecdotal evidence suggests that low doses of sodium channel blockers, such as carbamazepine, are effective in preventing attacks. Otherwise, there are no specific treatments for HM, and the use of medications for typical migraines with aura can be considered [Suzuki-Muromoto et al 2020].
Surveillance
Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires regularly scheduled follow up with the treating neurologist as well as educators and social services. The evaluations summarized in Table 6 are recommended.
SeLIE. Individuals are monitored clinically for seizures; ASMs are adjusted accordingly. The following are recommended depending on the ASM used: regular assessments of blood concentrations of medications, electrolytes, and vitamin D as well as liver enzymes and complete blood counts. Repeat EEGs are advised when subclinical seizures are suspected.
The response to ASMs can inform decisions on medication weaning. Notably, seizures in SeLIE typically subside by age two years, thus reducing the need for prolonged ASM use beyond this age.
Although heterozygous PRRT2 pathogenic variants are not known to be associated with an increased risk for developmental abnormalities, seizure disorders in general have a theoretic increased risk of developmental delay. Thus, monitoring early developmental progress is strongly advised.
Paroxysmal dyskinesias. Individuals with PKD or PKD with infantile convulsions (PKD/IC) can be monitored clinically every one to two years, particularly with respect to evaluating medication needs and dosing. More frequent visits may be necessary in individuals who have not achieved sufficient control of attacks or children whose medication doses are weight based.
Hemiplegic events. Individuals should be monitored clinically once a year. More frequent assessments may be needed for individuals who have not achieved sufficient control of attacks and/or whose medication doses are weight based.
Agents/Circumstances to Avoid
SeLIE. Treat fevers promptly.
PKD. Avoid stress, sleep deprivation, and anxiety (consistently reported as factors that increase the likelihood for PKD episodes) and other triggers to help prevent attacks and lower attack frequency.
HM. Use triptans and dihydroergotamine with caution due to their associated increased risk of ischemic vascular events.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Prenatal exposure to anti-seizure medications (ASMs) may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Because of the fetal risk related to use of ASMs, women with mild manifestations of PRRT2-related disorder may consider discontinuing ASMs prior to or during pregnancy. Alternatively, transitioning to a lower-risk ASM prior to pregnancy may be considered [Sarma et al 2016].
See MotherToBaby for more information on medication use during pregnancy.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
PRRT2-related disorder is typically caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner.
Note: Biallelic PRRT2 pathogenic variants, observed in <1% of individuals with PRRT2 pathogenic variants, are typically associated with a more severe phenotype (see Genetically Related Disorders). Risk to family members of a proband with biallelic PRRT2 pathogenic variants is not discussed in this section.
Risk to Family Members
Parents of a proband
About 90% of individuals diagnosed with
PRRT2-related disorder have an affected parent or other family member [
Ebrahimi-Fakhari et al 2015]. Reduced penetrance and variable expressivity lead to clinical variability within families.
About 10% of individuals diagnosed with PRRT2-related disorder have the disorder as the result of a de novo pathogenic variant.
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a de novo pathogenic variant.
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with a PRRT2-related disorder may appear to be negative because of reduced penetrance, variable expressivity, or failure to recognize the disorder in family members (particularly given that symptoms tend to become less frequent in adulthood). Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:
Offspring of a proband. Each child of an individual with a heterozygous PRRT2 pathogenic variant has a 50% chance of inheriting the pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PRRT2 pathogenic variant, the parent's family members may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once the PRRT2 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
PRRT2-Related Disorder: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
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|
128200 | EPISODIC KINESIGENIC DYSKINESIA 1; EKD1 |
|
602066 | CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS; ICCA |
|
605751 | SEIZURES, BENIGN FAMILIAL INFANTILE, 2; BFIS2 |
|
614386 | PROLINE-RICH TRANSMEMBRANE PROTEIN 2; PRRT2 |
Molecular Pathogenesis
PRRT2 encodes proline-rich transmembrane protein 2 (PRRT2), a membrane-bound protein that interacts with SNARE complexes that are integral to neurotransmitter release and help modulate the availability and activity of voltage-dependent sodium channels. Loss of PRRT2 function in cultured cells and transgenic mice leads to aberrant synaptic transmission, underscoring the essential role of PRRT2 in synaptic dynamics [Valente et al 2016, Michetti et al 2017, Tan et al 2018, Lu et al 2021]. Disruptions in this function can potentially trigger episodic neurologic disorders [Valente et al 2016, Lu et al 2021].
Studies have demonstrated that PRRT2 deficiency sensitizes the cerebellar cortex to spreading depolarization, thereby increasing the excitability of cerebellar neurons. This heightened excitability can disrupt normal neuronal firing patterns in deep cerebellar nuclei crucial for motor control. In mice lacking Prrt2, these disruptions are tightly linked to the onset and persistence of dyskinetic movements characteristic of conditions such as PRRT2-related paroxysmal kinesigenic dyskinesia [Lu et al 2021].
Mechanism of disease causation. Most reported PRRT2 pathogenic variants, including the common c.649dupC variant, lead to unstable messenger RNA or a truncated protein product that undergoes rapid degradation [Ebrahimi-Fakhari et al 2015]. The mechanism is thus consistent with a loss of function of PRRT2 (via haploinsufficiency).
PRRT2-specific laboratory technical considerations. The majority (70%-80%) of affected individuals have the frameshift variant c.649dupC [Ebrahimi-Fakhari et al 2015].
Table 7.
PRRT2 Pathogenic Variants Referenced in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Chapter Notes
Author Notes
The Movement Disorder Society Genetic mutation database (MDSGene) provides a comprehensive, systematic overview of published data on movement disorder patients, including patients with paroxysmal kinesigenic dyskinesia.
Recommendations on the Nomenclature of Genetic Movement Disorders are provided by the Task Force on the Nomenclature of Genetic Movement Disorders from the International Parkinson and Movement Disorders Society. Current recommendations are provided in Marras et al [2016] and Lange et al [2022].
Acknowledgments
The authors are grateful to the many patients and families who support research on PRRT2. The authors also thank Dr Christelle Moufawad El Achkar and Dr Christine Klein for contributions to an earlier version of this chapter.
Author History
Darius Ebrahimi-Fakhari, MD, PhD (2018-present)
Christine Klein, MD; University of Lübeck (2018-2024)
Christelle Moufawad El Achkar, MD; Harvard Medical School (2018-2024)
Vincente Quiroz, MD (2024-present)
Kathryn Yang, MD, FRCPC (2024-present)
Revision History
4 July 2024 (bp) Comprehensive update posted live
11 January 2018 (bp) Review posted live
16 August 2017 (def) Original submission
