The evolving spectrum ofPRRT2-associated paroxysmal diseases

Abstract

Next-generation sequencing has identified mutations in the PRRT2 (proline-rich transmembrane protein 2) gene as the leading cause for a wide and yet evolving spectrum of paroxysmal diseases. PRRT2 mutations are found in the majority of patients with benign familial infantile epilepsy, infantile convulsions and choreoathetosis and paroxysmal kinesigenic dyskinesia, confirming a common disease spectrum that had previously been suggested based on gene linkage analyses and shared clinical features. Beyond these clinical entities, PRRT2 mutations have been described in other childhood-onset movement disorders, different forms of seizures, headache disorders, and intellectual disability. PRRT2 encodes a protein that is expressed in the central nervous system and is thought to be involved in the modulation of synaptic neurotransmitter release. The vast majority of mutations lead to a truncated protein or no protein at all and thus to a haploinsufficient state. The subsequent reduction of PRRT2 protein may lead to altered synaptic neurotransmitter release and dysregulated neuronal excitability in various regions of the brain, resulting in paroxysmal movement disorders and seizure phenotypes. In this review, we examine the genetics and neurobiology of PRRT2 and summarize the evolving clinical and molecular spectrum of PRRT2-associated diseases. Through a comprehensive review of 1444 published cases, we provide a detailed assessment of the demographics, disease characteristics and genetic findings of patients with PRRT2 mutations. Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n = 206) constitute the vast majority of PRRT2-associated diseases, leaving 76 patients (5.3%) with a different primary diagnosis. A positive family history is present in 89.1% of patients; and PRRT2 mutations are familial in 87.1% of reported cases. Seventy-three different disease-associated PRRT2 mutations (35 truncating, 22 missense, three extension mutations, six putative splice site changes, and seven changes that lead to a complete PRRT2 deletion) have been described to date, with the c.649dupC frameshift mutation accounting for the majority of cases (78.5%). Expanding the genetic landscape, 15 patients with biallelic PRRT2 mutations and six patients with 16p11.2 microdeletions and a paroxysmal kinesigenic dyskinesia phenotype have been reported. Probing the phenotypic boundaries of PRRT2-associated disorders, several movement, seizure and headache disorders have been linked to PRRT2 mutations in a subset of patients. Of these, hemiplegic migraine emerges as a novel PRRT2-associated phenotype. With this comprehensive review of PRRT2-associated diseases, we hope to provide a scientific resource for informing future research, both in laboratory models and in clinical studies.

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

“…1,2 Family WF considerably expands the phenotypic spectrum of KCNA2 diseases to include mild wellcontrolled epilepsies and EA. All but one affected individual had infantile-onset seizures leading us initially to consider infantile convulsions choreoathetosis syndrome (ICCA), 25 although the movement disorder, EA, is clinically distinct from paroxysmal kinesigenic choreoathetosis. Their later evolution to GGE and focal epilepsy is also unusual for ICCA.…”

“…PRRT2 sequencing was negative in WF-III-4. 25 Many types of EA are recognized. EA1 is associated KCNA1 mutation and focal epilepsy, 26 while EA2 due to CACNA1A mutations is associated with generalized epilepsy.…”

16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability

“…Even in sporadic cases, the majority point and frameshift mutations of PRRT2 were inherited from unaffected parents (Ebrahimi‐Fakhari, Saffari, Westenberger, & Klein, 2015). In contrast, the two mutations in this study were de novo.…”

Benign Infantile Epilepsy Mimicking Reflex Anoxic Seizures in an Infant with PRRT2 Gene Mutation

“…To date, some 1500 patients with approximately seventy different PRRT2 mutations have been reported. Of these, 5.5% (79/1444) occurred de novo, while 87.1% (1258/1444) are familial in origin [2]. PRRT2 mutations have been mainly associated with Benign Familial Infantile Epilepsy, Paroxysmal Kinesigenic Dyskinesia and Infantile Convulsions and Choreoathetosis [2] and lately with benign myoclonus of early infancy [3] and paroxysmal hypnogenic dyskinesia (PHD) [4].…”