PRRT2-Associated Paroxysmal Movement Disorders

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.