PRRT2-Related Disorder

Excerpt

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.