PRRT2 Related Epilepsies: A Gene Review

Abstract

PRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.

Variable Phenotypes in the Same Patient with PRRT2-Associated Disorders

“…Functional studies demonstrate that these variants result in a reduction in the membrane localization of the PRRT2 protein and impaired interaction with SNAP25. 2,15,16 SCN1A-related conditions constitute a phenotypic spectrum that includes genetic epilepsy with febrile seizures plus (GEFS þ ), hemiplegic migraine, autism spectrum disorder, and developmental and epileptic encephalopathies. 17 Most of the variants show an autosomal dominant pattern of inheritance in which de novo and loss-of-function variants are the most frequently reported.…”

“…Functional studies demonstrate that these variants result in a reduction in the membrane localization of the PRRT2 protein and impaired interaction with SNAP25. 2 15 16…”

“…Self-limited (familial) infantile epilepsy (SeLIE) and paroxysmal kinesigenic dyskinesia (PKD), either occurring together or as single entities, are PRRT2 -associated disorders that constitute an evolving continuum with a common pathophysiology. 1 2 The clinical spectrum has expanded to include other paroxysmal diseases involving movement and headache disorders. 1 2 Around 5% of the patients have been reported to carry homozygous or compound heterozygous mutations in PRRT2 , exhibiting a more severe phenotype, including episodic ataxia, hemiplegic migraine, seizures, and intellectual disability, 1 3 4 although this number may be an underestimation.…”

“…1 2 The clinical spectrum has expanded to include other paroxysmal diseases involving movement and headache disorders. 1 2 Around 5% of the patients have been reported to carry homozygous or compound heterozygous mutations in PRRT2 , exhibiting a more severe phenotype, including episodic ataxia, hemiplegic migraine, seizures, and intellectual disability, 1 3 4 although this number may be an underestimation. PRRT2 variants are typically inherited in an autosomal dominant manner, and the vast majority of the cases are familial.…”

Editorial: Epigenetic and genetic mechanisms underlying cardiovascular diseases and neurodevelopmental disorders

“…BFIE is a familial epileptic syndrome, characterized with focal seizures that may evolve to secondary generalized tonic-clonic seizures. PRRT2 gene, encoding the proline-rich transmembrane protein 2, is a major causative gene for BFIE ( Massimino et al, 2023 ). Gu et al reported seven cases of BFIE effectively managed with anti-seizure medication, all stemming from pathogenic PRRT2 variants.…”