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.

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:

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).

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].

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.

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

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.

Mode of Inheritance

PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) caused by a heterozygous PRRT2 pathogenic variant or, in rare cases, 16p11.2 recurrent deletion (that includes PRRT2), are inherited in an autosomal dominant manner. (See 16p11.2 Recurrent Deletion for genetic counseling information specific to the 16p11.2 recurrent deletion.)

In rare cases (typically associated with a more severe phenotype), PRRT2-PxMD may be associated with biallelic PRRT2 pathogenic variants and inherited in an autosomal recessive manner [Ebrahimi-Fakhari et al 2015].

Autosomal Dominant Inheritance, PRRT2 Pathogenic Variant – Risk to Family Members

Parents of a proband

• About 90% of individuals diagnosed with a PRRT2-PxMD 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 a PRRT2-PxMD have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent PRRT2 de novo pathogenic variant.
• If the PRRT2 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, to date no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with a PRRT2-PxMD may appear to be negative because of 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 been performed on the parents of the proband.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or is known to be heterozygous for the PRRT2 pathogenic variant, the risk to the sibs is 50%. Reduced penetrance and variable expressivity are commonly observed, leading to phenotypic variability within families.
• If the PRRT2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• The sibs of a proband with clinically unaffected parents are still at increased risk for PRRT2-PxMD because of the possibility of reduced penetrance in a parent and the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with PRRT2-PxMD has a 50% chance of inheriting the PRRT2 pathogenic variant. Reduced penetrance and variable expressivity are commonly observed, leading to phenotypic variability within families.

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, his or her family members may be at risk.

Autosomal Recessive Inheritance, Biallelic PRRT2 Pathogenic Variants – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a PRRT2 pathogenic variant (a de novo pathogenic variant has not yet been documented to cause autosomal recessive PRRT2-PXMD).
• Heterozygotes may be affected with a PRRT2-PxMD or may be asymptomatic given reduced penetrance and clinical variability.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being a heterozygous carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes may be affected with a PRRT2-PxMD or may be asymptomatic given reduced penetrance and clinical variability.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 testing to be a personal decision, discussion of these issues may be helpful.

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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 PKD. Please refer to www.mdsgene.org.

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].

Acknowledgments

We are grateful to the many patients and families who support research on PRRT2. For his work on PRRT2, DEF acknowledges support from the Young Investigator Award Program at Ruprecht-Karls-University Heidelberg Faculty of Medicine, the Daimler and Benz Foundation (Daimler und Benz Stiftung, Ladenburg, Germany), the Reinhard-Frank Foundation (Reinhard-Frank-Stiftung, Hamburg, Germany), and the Fred-Lovejoy Research and Education Fund (Boston, MA, USA).

CK acknowledges support from the Hermann and Lilly Schilling Foundation, the German Research Foundation, and the University of Lübeck's intramural programs.

Revision History

• 11 January 2018 (bp) Review posted live
• 16 August 2017 (def) Original submission