Prrt2-Associated Paroxysmal Movement Disorders
Summary
Clinical characteristics.
PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) include paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), and hemiplegic migraine (HM). In addition, PRRT2 pathogenic variants have been identified in other childhood-onset movement disorders and different types of seizures, suggesting that the understanding of the spectrum of PRRT2-PxMD is still evolving. The paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and less commonly ballismus. The seizures of BFIE are usually focal with or without generalization. Thirty percent of PRRT2-associated PKD is associated with BFIE and is referred to as PKD/IC.
Diagnosis/testing.
The diagnosis of PRRT2-PxMD is established in a proband who has one of the following three findings on molecular genetic testing: a PRRT2 heterozygous pathogenic variant (~99% of affected individuals); the 16p11.2 recurrent deletion that includes PRRT2 (<1% of affected individuals); or biallelic PRRT2 pathogenic variants (<1% of affected individuals, typically those with a more severe phenotype).
Management.
Treatment of manifestations: PKD attack frequency is reduced or prevented by treatment with low doses of antiepileptic drugs (AEDs). Avoiding stress, sleep deprivation, anxiety, and other triggers that can precipitate PKD episodes can help prevent attacks and can lower attack frequency. For BFIE, seizure frequency is decreased by therapeutic doses of AEDs; seizures lasting longer than five minutes or seizure clusters may respond to use of benzodiazepines. Seizures tend to spontaneously remit by age two years.
Surveillance: Individuals with PKD or PKD/IC can be monitored clinically every one to two years, particularly with respect to evaluating medication needs and dosing. Individuals with BFIE are monitored clinically for seizures; AEDs are adjusted accordingly.
Agents/circumstances to avoid: PKD: Avoid triggers known to precipitate attacks.
Pregnancy management: Prenatal exposure to AEDs 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 AED during pregnancy should ideally take place prior to conception.
Genetic counseling.
PRRT2-PxMD caused by a heterozygous PRRT2 pathogenic variant or, rarely, the 16p11.2 recurrent deletion (that includes PRRT2) is inherited in an autosomal dominant manner. Rarely PRRT2-PxMD (typically associated with a more severe phenotype) is inherited in an autosomal recessive manner. For autosomal dominant PRRT2-PxMD: approximately 90% of pathogenic variants are inherited and 10% are de novo. Each child of an individual with PRRT2-PxMD has a 50% chance of inheriting the PRRT2 pathogenic variant. Once the PRRT2 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible; however, reduced penetrance and variable expressivity lead to phenotypic variability within families.
Diagnosis
Suggestive Findings
PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) should be considered in individuals with any one of the following four phenotypes and/or in individuals with a paroxysmal movement disorder and a positive family history of any of the four phenotypes:
Paroxysmal Kinesigenic Dyskinesia (PKD)
PKD characterized by the following clinical and supportive findings (adapted from Bruno et al [2004]):
- Clinical findings. Sudden attacks of unilateral or bilateral involuntary movements (dyskinesias that can include a combination of dystonia, chorea, ballism, or athetosis) and the following:
- Onset between ages one and 20 years
- A kinesigenic trigger (e.g., sudden voluntary movements or being startled)
- An aura preceding attacks (10% of individuals)
- Short duration (typically <1 minute)
- High frequency (sometimes as many as 100 times/day)
- No loss of consciousness or pain during attacks
- Prevention or control with phenytoin or carbamazepine
- Supportive findings
- Normal neurologic examination between attacks
- Normal brain MRI
- No EEG changes during the attacks
Benign Familial Infantile Epilepsy (BFIE)
BFIE characterized by the following clinical and supportive findings [Watanabe et al 1987, Vigevano 2005, Specchio & Vigevano 2006]:
- Clinical findings. Complex partial seizures or localization-related epilepsy (focal, typically with altered awareness, and a unilateral motor component that can involve either side of the body in the same individual) with the following:
- Onset in the first year of life (most commonly 4-12 months)
- Either spontaneous or occuring in the context of fever [Scheffer et al 2012]
- Can occur in clusters of multiple seizures per day: up to eight to ten seizures per day occurring every two to three hours on average
- Excellent response to antiepileptic drugs (AEDs)
- Resolution by age two years
- Supportive findings
- Otherwise normal development and normal developmental outcome
- Normal neurologic examination
- Normal brain imaging and EEG background signal
Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC)
PKD/IC characterized by both of the following phenotypes:
- Paroxysmal movement disorder that meets criteria for PKD
- Seizures that meet criteria for BFIE
Hemiplegic Migraine (HM)
HM (The International Classification of Headache Disorders ICHD-3 beta [Headache Classification Committee 2013]) characterized by:
- Migraine with aura
- Aura that includes some degree of hemiparesis and may be prolonged
Note: Heterozygous PRRT2 pathogenic variants have been described in persons with HM who represent simplex cases (i.e., a single occurrence in a family) [Ebrahimi-Fakhari et al 2015].
Establishing the Diagnosis
The diagnosis of PRRT2-PxMD is established in a proband who meets clinical criteria and has one of the following on molecular genetic testing (see Table 1):
- A PRRT2 heterozygous pathogenic variant (~99% of affected individuals) [Chen et al 2011, Wang et al 2011, Ebrahimi-Fakhari et al 2015]
- The 16p11.2 recurrent deletion that includes PRRT2 (<1% of affected individuals) [Dale et al 2012, Silveira-Moriyama et al 2013, Weber et al 2013, Termsarasab et al 2014, Ebrahimi-Fakhari et al 2015]
- Biallelic PRRT2 pathogenic variants (<1% of affected individuals) [Ebrahimi-Fakhari et al 2015] observed in rare instances of autosomal recessive inheritance in individuals with a more severe phenotype [Labate et al 2012, Delcourt et al 2015]
Molecular genetic testing approaches can include gene-targeted testing (typically targeted sequencing of PRRT2 or a multigene panel) and comprehensive genomic testing (chromosomal microarray analysis [CMA] and genomic sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from a wide range of other paroxysmal disorders are likely to be diagnosed using either a multigene panel or genomic testing (i.e., exome sequencing) (see Option 2).
Option 1
When the phenotype and family history suggest the diagnosis of PRRT2-PxMD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
- Single-gene testing. Sequence analysis of PRRT2 is performed first. If no pathogenic variant is found, gene-targeted deletion/duplication analysis should be performed next.
- A multigene panel for PKD, BFIE PKD/IC, or HM may also be considered.Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Given the rarity of PRRT2-associated paroxysmal disorders, clinicians should ensure that PRRT2 is included in gene panels for the phenotypes observed in this wide spectrum of neurologic findings. (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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For more information on multigene panels click here.
Option 2
When the diagnosis of PRRT2-PxMD has not been considered, comprehensive genomic testing is likely to be the diagnostic modality selected. Genomic sequencing (when clinically available) includes exome sequencing and genome sequencing.
For more information on comprehensive genomic testing click here.
Table 1.
Molecular Genetic Testing Used in PRRT2-Associated Paroxysmal Movement Disorders
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method 3 |
|---|---|---|
| PRRT2 | Sequence analysis 4 | 99% |
| Gene-targeted deletion/duplication analysis 5 | <1% | |
| CMA 6 | <1% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Ebrahimi-Fakhari et al [2015]
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes, such as the 16p11.2 recurrent deletion, may not be defined by these methods.
- 6.
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays detects copy number variants and defines breakpoints of large deletions, including the 16p11.2 recurrent deletion.
Clinical Characteristics
Clinical Description
The core phenotypes of PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) include paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), and hemiplegic migraine (HM). In addition, PRRT2 pathogenic variants have been identified in other childhood-onset movement disorders and different types of seizures, including a small number of individuals who meet clinical criteria for paroxysmal nonkinesigenic dyskinesia (PNKD) [Liu et al 2012, Becker et al 2013, Liu et al 2013, Wang et al 2013, Delcourt et al 2015], paroxysmal exertion-induced dyskinesia [Liu et al 2012], and episodic ataxia [Gardiner et al 2012, Labate et al 2012, Delcourt et al 2015]. Thus, it is likely that the understanding of the spectrum of associated phenotypes is still evolving [Ebrahimi-Fakhari et al 2015].
Paroxysmal Kinesigenic Dyskinesia (PKD)
To date, the primary paroxysmal movement disorder of PRRT2-PxMD is PKD (see Suggestive Findings, PKD). Paroxysmal attacks are often characterized by dystonia, followed by choreoathetosis, and rarely ballism. Attacks often occur bilaterally. The arms are the most commonly involved, followed in decreasing order by involvement of the legs, trunk, face, and neck.
Onset of PRRT2-PKD is in childhood or adolescence (mean age: 10.3±4.9 [SD] years; range: 1-20 years) [Ebrahimi-Fakhari et al 2015].
The most common triggers are sudden voluntary movements, stress, being startled, intent to perform a voluntary movement, and sleep deprivation. While caffeine and alcohol are precipitating factors in a few affected individuals and attacks at rest are reported in approximately 2% of affected individuals, both of these triggers are more typical of paroxysmal nonkinesigenic dyskinesia (PNKD) than PKD.
A nonspecific aura precedes PKD attacks in about 10% of individuals. Reported aura symptoms include a crawling sensation in the affected limb, paresthesias, or nonspecific epigastric discomfort.
Attacks are usually brief – in the range of a few seconds – but in some individuals last five minutes or more.
The frequency of attacks is highly variable, ranging from 100 per day to one per week [Ebrahimi-Fakhari et al 2015].
Attacks tend to become less frequent with age and often respond well to anticonvulsants such as carbamazepine.
Benign Familial Infantile Epilepsy (BFIE)
The seizures are complex partial seizures or localization-related epilepsy (see Suggestive Findings, BFIE). Ictal patterns have been described as focal; onset has been reported in temporal, central, parietal, and occipital areas, with or without secondary generalization [Caraballo et al 2002].
Seizures may occur in clusters with multiple complex partial seizures per day. Less common are motor arrest, decreased responsiveness, and automatisms [Watanabe et al 1987]. Seizures rarely progress into status epilepticus. While respiratory depression can occur either during seizures or from medications including benzodiazepines, sudden unexpected death in epilepsy and long-term sequelae have not been reported.
In the vast majority of individuals the interictal EEG is unremarkable. In rare instances interictal focal epileptiform discharges may be seen, including bilateral centrotemporal spikes [Seo & You 2016], bilateral parietotemporal spikes [Torisu et al 2014], and unilateral frontocentral spikes [El Achkar et al 2017].
Epilepsy-related brain MRI abnormalities are not reported.
Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC)
A seizure disorder in the form of BFIE is present in about 30% of PRRT2-PKD, leading to the diagnosis of PKD/IC. It is currently unknown how frequently BFIE evolves into PKD/IC.
Hemiplegic Migraine (HM)
HM falls within the classification of migraines with aura, characterized by an aura that localizes to the cerebral cortex. These auras comprise the following (in order of frequency):
- Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
- Sensory loss (e.g., numbness or paresthesias)
- Dysphasia
HM additionally presents with motor symptoms in the form of some degree of hemiparesis.
Attack frequency often declines over time. Many affected individuals even report a complete remission during adulthood. Improvement during pregnancy has also been observed [Bruno et al 2004].
Genotype-Phenotype Correlations
No clear evidence for genotype-phenotype correlations exists for PKD, BFIE, PKD/IC, and HM, the four core PRRT2-PxMD phenotypes [Ebrahimi-Fakhari et al 2015]. Considerable variation in phenotype is seen both within and between families with the same pathogenic PRRT2 variant.
Individuals with a 16p11.2 deletion who have PRRT2-PKD tend to have additional clinical features including developmental delay, intellectual disability, and/or autism spectrum disorder [Dale et al 2012, Silveira-Moriyama et al 2013, Weber et al 2013, Termsarasab et al 2014].
Individuals with biallelic PRRT2 pathogenic variants tend to have a more severe phenotype that often includes intellectual disability, episodic ataxia, and different seizure types [Labate et al 2012, Delcourt et al 2015].
Penetrance
The penetrance for PRRT2-PKD has been estimated to be 60%-90% [van Vliet et al 2012]; thus, individuals with a known PRRT2 pathogenic variant may be clinically unaffected.
The penetrance for PRRT2-BFIE and PRRT2-HM is unknown.
Nomenclature
Paroxysmal kinesigenic dyskinesia (PKD) was formerly known as paroxysmal kinesigenic choreoathetosis (PKC).
Benign familial infantile epilepsy (BFIE) is also known as benign familial infantile seizures (BFIS).
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) was formerly known as infantile convulsions and choreoathetosis (ICCA).
Current recommendations are use of the designation PRRT2-PxMD for paroxysmal movement disorders associated with PRRT2 [Marras et al 2016].
Prevalence
The PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) are rare.
Prevalence for PKD, the most common of the paroxysmal movement disorders (including both PRRT2-PxMD and PKD of unknown or secondary cause), has been estimated at 1:150,000 individuals [Ebrahimi-Fakhari et al 2015].
To date approximately 600 individuals with PRRT2-BFIE, 560 with PRRT2-PKD, and 210 with PRRT2-PKD/IC have been reported [Ebrahimi-Fakhari et al 2015].
The majority of these individuals are of Asian ethnicity from China and Japan, followed by individuals from North America and Europe.
PRRT2-PKD appears to be more common in males with about 1.5-fold more males reported than females.
Differential Diagnosis
PRRT2 pathogenic variants are found in the majority of individuals with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), confirming a common disease spectrum that had previously been suspected based on linkage analyses [Ebrahimi-Fakhari et al 2015].
Familial hemiplegic migraine, defined as the presence of at least one first-degree relative with identical attacks, has been associated with pathogenic variants in CACNA1A (designated FHM1), ATP1A2 (FHM2), and SCN1A (FHM3).
Table 2.
Genetic Disorders to Consider in the Differential Diagnosis of PRRT2-Associated Paroxysmal Movement Disorders
| Disorder | Gene(s) | MOI | Clinical Features of the Disorder | |
|---|---|---|---|---|
| Overlapping w/PRRT2-PXMD | Distinguishing from PRRT2-PXMD | |||
| Paroxysmal nonkinesigenic dyskinesia (PNKD) | PNKD | AD | Paroxysmal dyskinesias | No kinesigenic trigger. Attacks:
|
| Paroxysmal exertion-induced dyskinesia (PED) | SLC2A1 | AD (SLC2A1-PxMD) | Paroxysmal dyskinesias | Attacks:
|
| GLUT1 deficiency syndrome | SLC2A1 | AD | Paroxysmal dyskinesias | Includes a spectrum of manifestations:
|
| Episodic ataxia type 1, episodic ataxia type 2 (OMIM 108500) | KCNA1 CACNA1A SLC1A3 | AD | Paroxysmal ataxia | Brief intermittent episodes of ataxia of variable duration |
| ADCY5-related dyskinesia | ADCY5 | AD | Paroxysmal dyskinesias | Attacks:
|
| Familial hemiplegic migraine | CACNA1A ATP1A2 SCN1A | AD | Paroxysmal hemiplegia | Positive family history |
| Alternating hemiplegia of childhood (See ATP1A3-Related Neurologic Disorders.) | ATP1A2 ATP1A3 | AD | Paroxysmal hemiplegia and dystonia |
|
| Wilson disease | ATP7B | AR | Dyskinesias |
|
| Simple febrile seizures, complex febrile seizures, genetic epilepsy with febrile seizures plus (GEFS+) (see SCN1A-Related Seizure Disorders) | SCN1A, SCN1B, and others | AD or multifactorial | Seizures |
|
| Benign (familial) neonatal infantile epilepsy (see KCNQ2-Related Disorders and KCNQ3-Related Disorders) | KCNQ2, KCNQ3 | AD | Seizures | Earlier age of onset |
| Benign (familial) neonatal infantile epilepsy (OMIM: 607745) | SCN2A | AD | Seizures | Earlier age of onset |
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; PED = paroxysmal exertion-induced dyskinesia
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a PRRT2-associated paroxysmal movement disorder (PRRT2-PxMD), the following evaluations are recommended if they have not already been completed:
- Consultation with a neurologist who is a specialist in epilepsy and/or movement disorders
- Patients with PKD. Consider MRI to evaluate for other causes (e.g., hemorrhage, stroke, focal cortical dysplasia).
- Patients with atypical or ambiguous paroxysmal movements. Consider EEG to evaluate for possible seizures.
- Patients with seizures. Consider:
- Basic laboratory tests to evaluate for other causes of seizures;
- EEG to confirm normal background for age (capturing seizures on EEG may not be necessary if events are clinically consistent with seizures).
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
PKD
Attack frequency is reduced or prevented by treatment with low doses of antiepileptic drugs (AEDs).
- Carbamazepine is often effective. Note that doses lower than those used to treat epilepsy are usually sufficient.
- Other AEDs including phenytoin, valproate, oxcarbazepine, lamotrigine, levetiracetam, or topiramate may also be effective.
Avoiding stress, sleep deprivation, anxiety, and other triggers that increase the likelihood for PKD episodes can help prevent attacks and can lower attack frequency.
No other pharmacotherapies or non-pharmacologic treatments have been investigated systematically.
BFIE
Seizure frequency is decreased by therapeutic doses of AEDs. Although response to carbamazepine or oxcarbazepine has not been well studied, these tend to be the preferred AEDs given the known favorable response in PKD and anecdotal response in HM.
During seizures lasting longer than five minutes or seizure clusters, benzodiazepines including lorazepam, diazepam, or midazolam can be used. Anecdotally, however, the response to benzodiazepines in PRRT2-associated seizures is less robust.
In patients with BFIE, no specific interventions are known to decrease the risk of later developing PKD.
Prevention of Secondary Complications
PKD. Falls and interference with activities such as driving are potential secondary complications. Counseling is needed to prevent these potential secondary complications.
Surveillance
PKD. Individuals with PKD or 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 who need weight-based adjustment of medication doses.
BFIE. Patients are monitored clinically for seizures and AEDs are adjusted accordingly. Depending on the agent used, medication serum levels – as well as liver enzymes, complete blood count, electrolytes, and vitamin D levels – should be monitored periodically. Repeat EEGs are only recommended when there is concern for subclinical seizures.
While heterozygous PRRT2 pathogenic variants are not known to be associated with an increased risk for developmental abnormalities, any seizure disorder carries the theoretic increased risk of developmental delay; thus, early developmental surveillance is recommended.
Agents/Circumstances to Avoid
PKD. Stress, sleep deprivation, and anxiety are consistently reported as factors that increase the likelihood for PKD episodes; avoiding these or other triggers can help prevent attacks and can lower attack frequency.
BFIE. Treat fevers promptly.
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 AEDs 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 AED during pregnancy should ideally take place prior to conception. Because of the fetal risk related to anticonvulsant therapy, women with mild manifestations of PKD may consider discontinuing anticonvulsant therapy prior to or during pregnancy. Alternatively, transitioning to a lower-risk AED 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.